Glycinamide derivatives, processes for their preparation and medicines containing them

ABSTRACT

The present invention relates to compounds of formula:   &lt;IMAGE&gt;   which are agonists of cholecystokinin receptors and pharmaceutical compositions containing them.

The present invention relates to glycinamide derivatives, to a processfor their preparation and to the medicines containing them.

More particularly, the subject of the present invention is newnon-peptide agonists of cholecystokinin (CCK) receptors.

CCK is a peptide which, in response to food ingestion, is secreted atthe peripheral level and participates in the control of many digestiveprocesses (Crawley J. N. et al., Peptides, 1994, 15 (4), 731-735).

CCK was subsequently identified in the brain and could be the comonestneuropeptide acting as neuromodulator of cerebral functions bystimulation of receptors of CCK-B type (Crawley J. N. et al., Peptides,1994, 15 (4), 731-735). CCK interacts in the central nervous system withthe neuronal transmission mediated by dopamine (Crawley J. N. et al.,ISIS Atlas of Sci., Pharmac., 1988, 84-90). It is also involved inmechanisms involving acetylcholine, gaba (4-aminobutyric acid),serotonin, opioids, somatostatin or substance P and in ionic channels.

Its administration causes physiological modifications: palpebral prosis,hypothermia, hyperglycaemia or catalepsy, and behavioural modifications:hypolocomotoricity, decrease in exploratory behaviour, analgesia,modification of the ability to learn, modification of sexual behaviourand satiation.

CCK exerts its biological activity via at least two types of receptors:CCK-A receptors, located mainly on the periphery, and CCK-B receptors,present essentially in the cerebral cortex. Peripheral-type CCK-Areceptors are also present in certain regions of the central nervoussystem, including the area postrema, the nucleus of the solitary tractand the interpeduncular nucleus (Moran T. H. et al., Brain Research,1986, 362, 175-179; Hill D. R. et al., J. Neurosci., 1990, 10,1070-1081); with, however, differences in type (Hill D. R. et al., J.Neurosci., 1990, 10, 1070-1081; Mailleux P. et al., Neurosci. Lett.,1990, 117, 243-247; Barrett R. W. et al., Mol. Pharmacol., 1989, 36,285-290; Mercer J. G. et al., Neurosci. Lett., 1992, 137, 229-231; MoranT. H. et al., TIPS, 1991, 12, 232-236).

At the periphery, via CCK-A receptors (Moran T. H. et al., BrainResearch, 1986, 362, 175-179), CCK delays gastric dumping, modulatesintestinal motility, stimulates vesicular contraction, increases bilesecretion and controls pancreatic secretion (McHugh P. R. et al., Fed.Proc., 1986, 45 , 1384-1390; Pendleton R. G. et al., J. Pharmacol. Exp.Ther., 1987, 241, 110-116).

CCK could have an effect, in certain cases, on arterial pressure andcould influence the immune systems.

The role of CCK in the signal for satiation is supported by the factthat the CCK plasma concentrations, which depend on the composition ofthe meals (high concentrations of proteins or lipids), are, after themeals, greater than those observed before the meals (Izzo R. S. et al.,Regul. Pept., 1984, 9, 21-34; Pfeiffer A. et al., Eur. J. Clin. Invest.,1993, 23, 57-62; Lieverse R. J.). Significantly high CCK plasma levelshave been described in anorexic and/or bulimic patients (Philipp E. etal., Life Sc., 1991, 48, 2442-2450; Geraciotti T. D. Jr. et al., N.Engl. J. Med., 1988, 319, 683-688). In bulimic patients, there is adecrease in the secretion of CCK induced by a meal and a lowering in CCKconcentrations in the cerebrospinal fluid (Geraciotti T. D. Jr. et al.,N. Engl. J. Med., 1988, 319, 683-688).

On the basis of this evidence of the key role of CCK in the peripheralsignal for satiation, the usefulness of agonists and antagonists of CCKas medicine in the treatment of certain disorders of food behaviour, ofobesity and of diabetes is indisputable. An agonist of CCK receptors canalso be used in therapeutics in the treatment of disorders of emotional,sexual and memory behaviour (Itoh S. et al., Drug. Develop. Res., 1990,21, 257-276), of schizophrenia, of psychoses (Crawley J. N. et al., ISISAtlas of Sci., Pharmac., 1988, 84-90 and Crawley J. N., TIPS, 1991, 12,232-265), of Parkinson's disease, of tardive dyskinesias and of variousdisorders of the gastrointestinal sphere (Drugs of the Future, 1992,17(3), 197-206).

Agonists of the CCK receptor are described in the literature. Forexample, certain products having such properties are described inEP-A-0,383,690 and WO 90/06937.

The majority of the CCK-A agonists described to date have a peptidenature. Thus, FPL 14294, derived from CCK-7, a powerful CCK-A agonistwhich is nonselective with respect to CCK-B receptors, has a powerfulinhibiting activity on food uptake in rats and in dogs, after intranasaladministration (Simons R. D. et al., Pharmacol. Biochem. Behav., 1994,47(3), 701-708; Kaiser E. F. et al., FASEB, 1991, 5, A864). Likewise, ithas been shown that A-71623, a tetrapeptide which is a selective agonistof CCK-A receptors, is effective in anorexia models over a period of 11days and results in a significant reduction in weight gain with respectto the control in rodents and cynomolgus monkeys (Asin K. E. et al.,Pharmacol. Biochem. Behav., 1992, 42, 699-704). In the same way,structural analogues of A 71623, which are highly effective andselective for CCK-A receptors, possess a powerful anorexigenic activityin rats (Elliott R. L. et al., J. Med. Chem., 1994, 37, 309-313; ElliottR. L. et al., J. Med. Chem., 1994, 37, 1562-1568).

Patent Application WO 91/13874 describes a series of glycinamidederivatives having an affinity for CCK receptors. More particularly,these compounds are described as selective antagonists of theCCK-B/gastrin receptor (XIIth Int. Symp. Med. Chem., Basle, 1992).

It has now surprisingly been found that a series of glycinamidederivatives has a powerful agonist activity for CCK-A receptors.

The compounds according to the invention have formed the subject ofsystematic studies in order to characterize:

their potentiality in displacing ¹²⁵ I!-CCK from its binding sitespresent on rat pancreas membranes (CCK-A receptor) or from 3T3 cellsexpressing the recombinant human CCK-A receptor,

their selectivity with respect to the CCK-B receptor present on guineapig cortex membranes, the compounds being selective or non-selectiveligands of CCK-A receptors,

their agonist property towards CCK-A receptors, through their ability toinduce the in vitro secretion of amylase by rat pancreas cells or tocause the in vivo dumping of the gall bladder in mice or, still in vivo,to block gastric dumping in mice,

their effect on food consumption in rats.

Thus, the present invention relates to compounds of formula: ##STR2## inwhich R_(I) represents a (C₃ -C₈) alkyl; an arylalkyl -Alk-Ar₁, whereAlk represents an alkylene containing 1 to 4 carbon atoms and Ar₁represents a phenyl group or a heterocycle optionally substituted by ahalogen, a (C₁ -C₃) alkyl, a (C₁ -C₃) alkoxy, a trifluoromethyl or ahydroxyl; a cycloalkylalkyl in which the alkyl is (C₁ -C₄) and thecycloalkyl is (C₃ -C₁₀); a (C₃ -C₁₀) cycloalkyl optionally substitutedby a hydroxyl, a (C₁ -C₃) alkoxy or a (C₁ -C₃) alkyl, it being possiblefor the said alkyl to substitute the same carbon atom twice; analkoxyalkyl in which the alkoxy is (C₁ -C₄) and the alkyl is (C₂ -C₅);or a group (AB)N--CO--(CH₂)_(r) --, where A is a (C₁ -C₃) alkyl, B is a(C₁ -C₃) alkyl or a phenyl or else A and B form, with the nitrogen atomto which they are bonded, a heterocycle chosen from pyrrolidine,piperidine and morpholine, and R is 1, 2 or 3;

R_(II) represents hydrogen; a (C₁ -C₆) alkyl; a (C₁ -C₅) hydroxyalkyl; agroup --(CH₂)_(m) --COR₂ in which m is an integer from 1 to 3 and R₂represents a hydroxyl, a (C₁ -C₄) alkoxy group, a benzyloxy group or agroup --NR₃ R₄ in which R₃ or R₄ independently represent hydrogen, a (C₁-C₄) alkyl or constitute, with the nitrogen atom to which they arebonded, a heterocycle chosen from pyrrolidine, piperidine andmorpholine; an aralkyl group --(CH₂)_(n) --Ar₂ in which n is equal to 0or represents an integer from 1 to 4 and Ar₂ represents a phenyl or aheterocycle optionally substituted by a halogen, a (C₁ -C₃) alkyl, a (C₁-C₃) alkoxy, a trifluoromethyl, a hydroxyl or a benzyloxy; acycloalkylalkyl in which the alkyl is (C₁ -C₄) and the cycloalkyl is (C₃-C₁₀); a (C₁ -C₄) aminoalkyl; a group R--CO--NH--(CH₂)_(x) -- in which xrepresents an integer from 1 to 4 and R represents a (C₁ -C₄) alkyl, aphenyl, a benzyl, a 2-phenylethenyl or a benzyloxy, the aromatic ringsoptionally being substituted by a halogen, a (C₁ -C₃) alkyl, a (C₁ -C₃)alkoxy, a trifluoromethyl, a hydroxyl or a sulpho or carboxyl group; aguanidino(C₁ -C₄)alkyl; an imidazolyl (C₁ -C₃) alkyl; an alkylthioakylin which the alkyls are (C₁ -C₃); an aralkylthioalkyl in which the arylpart is optionally heterocyclic and the alkyl parts are (C₁ -C₃), thearyl optionally being substituted by a halogen, a (C₁ -C₃) alkyl, a (C₁-C₃) alkoxy, a trifluoromethyl or a hydroxyl; a benzyloxyalkyl in whichthe alkyl is (C₁ -C₃) and the phenyl is optionally substituted by ahalogen, a hydroxyl, a (C₁ -C₃) alkoxy, a (C₁ -C₃) alkyl, atrifluoromethyl, a nitrile or a nitro;

R_(III) represents a naphthyl group; a quinolyl group; an isoquinolylgroup; an indolyl group which is unsubstituted, substituted on a carbonor substituted on the nitrogen by a (C₁ -C₄) alkylcarbonyl group, by agroup --(CH₂)_(p) --COR₅, p being an integer from 0 to 4 and R₅representing OR'₅ or NR'₅ R"₅ with R'₅ and R"₅, which may or may not beidentical, representing hydrogen or a (C₁ -C₄) alkyl or else R'₅ and R"₅form, together with the nitrogen atom to which they are bonded, apiperidine, by a (C₁ -C₄) hydroxyalkyl, by a (C₂ -C₆) alkoxyalkyl, by a(C₂ -C₄) cyanoalkyl, by a tetrahydropyranyl, by anadamantylaminocarbonyl (C₁ -C₄) alkyl or by a chain --(CH₂)_(q) --, qbeing an integer from 2 to 4, one of the carbons of which substitutesthe phenyl ring of the indole group in order to constitute a ring;

Ar represents a 2-methoxy-3-pyridyl, 4-methoxy-5-pyrimidinyl or2-methoxyphenyl group containing at least two other substituents chosenfrom a (C₁ -C₃) alkyl, a (C₁ -C₃) alkoxy, a halogen atom and atrifluoromethyl; or Ar represents a naphthyl group;

or else R_(I) and R_(II) together constitute a group ##STR3## in which grepresents 0, 1 or 2 and Z represents a (C₁ -C₄) alkyl, a (C₁ -C₃)alkoxy or a halogen;

or optionally one of their salts.

One advantageous class of products is represented by the followingformula: ##STR4## in which R_(II) and R_(III) are as defined above for(I) and R_(Ia) represents a (C₅ -C₈) alkyl; an arylalkyl -Alk-Ar₁, whereAlk represents an alkylene containing 1 to 4 carbon atoms and Ar₁represents a phenyl group or a heterocycle optionally substituted by ahalogen, a (C₁ -C₃) alkyl, a (C₁ -C₃) alkoxy, a trifluoromethyl or ahydroxyl; a cycloalkylalkyl in which the alkyl is (C₁ -C₄) and thecycloalkyl is (C₃ -C₁₀); a (C₃ -C₁₀) cycloalkyl which is optionallysubstituted by a (C₁ -C₃) alkoxy, a hydroxyl or a (C₁ -C₃) alkyl, itbeing possible for the said alkyl to substitute the same carbon atomtwice; an alkoxyalkyl in which the alkoxy is (C₁ -C₄) and the alkyl is(C₂ -C₅); or a group (AB)N--CO--(CH₂)_(r) --, where A is a (C₁ -C₃)alkyl, B is a (C₁ -C₃) alkyl or a phenyl or else A and B form, with thenitrogen atom to which they are bonded, a heterocycle chosen frompyrrolidine, piperidine and morpholine, and r is 1, 2 or 3, oroptionally one of their salts.

The addition salts of these compounds are those obtained, ifappropriate, with inorganic or organic acids and bases; the nontoxicpharmaceutically acceptable salts are preferred but other salts, whichcan be used for isolating or purifying the compounds of formula (I) arealso within the invention.

In the preceding and following definitions, the alkyl radicals arestraight- or branched-chain.

When Ar₁ or Ar₂ represents a heterocycle, this heterocycle is preferablyselected from pyridine, pyrimidine, pyrazine or pyridazine.

When R_(II) represents aralkylthioalkyl, the aryl group is preferablyselected from phenyl, pyridine, pyrimidine, pyrazine and pyridazine.

In the formula (I), the halogen atoms are preferably chlorine, bromineor fluorine atoms.

The compounds of formula (I) containing one or a number of asymmetriccentres exhibit isomeric forms. The racemics and the enantiomers orstereoisomers of these compounds also form part of the invention.

When the substituent R_(II) is other than hydrogen, the enantiomers inwhich the carbon carrying R_(II) is in the R configuration arepreferred.

When R_(I) and R_(II) together constitute a group ##STR5## in which Zand g are as defined for (I), the enantiomers in which the carboncarrying R_(II) is in the S configuration are preferred.

A group of compounds having a better agonist activity for CCK-Areceptors is that in which R_(I) represents a (C₃ -C₈) alkyl, betterstill is that in which R_(I) represents a (C₄ -C₈) alkyl and a preferredgroup is that in which R_(I) represents a (C₅ -C₈) alkyl and aparticularly preferred group is that in which R_(I) is a (C₅ -C₇)cycloalkyl.

The compounds of formula (I) in which Ar represents a naphthyl group andR_(I) is R_(Ia) as defined above form another group of preferredcompounds.

The compounds of formula (I) in which Ar represents a 2-methoxyphenylradical substituted by at least two substituents, chosen from (C₁ -C₄)alkyl, (C₁ -C₃) alkoxy, a halogen atom or a trifluoromethyl group, areadvantageous compounds.

The compounds of formula (I) in which Ar represents a 2-methoxylohenylradical substituted on the aromatic ring by a methyl and a secondmethoxy are very advantageous compounds.

The compounds of formula (I) in which R_(III) represents a 2-indolylwhich may or may not be substituted on the N are particularlyadvantageous.

The compounds of formula (I) in which R_(I) represents a C₅ alkyl or aC₆ cycloalkyl, R_(II) represents a benzyloxyalkyl or a cycloalkylalkyl,R_(III) represents a substituted 2-indolyl and Ar represents a2,6-dimethoxy-4-methylphenyl are more particularly preferred.

The following compounds are even more particularly preferred:

EXAMPLE 3 (R)-N- 1-(2,6-Dimethoxy-4-methylphenyl)pentylcarbamoyl!ethyl!-1H-indole-2-carboxamideEXAMPLE 6 3- 2-(Cyclohexylmethyl)(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylcarbamoyl!indol-1-yl!propionicacid EXAMPLE 8 N-{(2,6-Dimethoxy-4-methylphenyl)pentylcarbamoyl!methylcarbamoyl}-1H-indole-2-carboxamideEXAMPLE 9 Methyl{2-(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl!methylcarbamoyl!indol-1-yl}acetateEXAMPLE 10 {2-(2,6-Dimethoxy-4-methylphenyl)pentylcarbamoyl!methylcarbamoyl!indol-1-yl}aceticacid EXAMPLE 13 (R)- 2-{1-(2,6-Dimethoxy-4-methylphenyl)pentylcarbamoyl!ethylcarbamoyl}indol-1-yl!aceticacid EXAMPLE 16 (R)-4-{(2,6-Dimethoxy-4-methylphenyl)pentylcarbamoyl}-4-(1H-indole-2-carbonyl)amino!butyric acid EXAMPLE 19 (R)-N-{1-(2,6-Dimethoxy-4-methylphenyl)pentylcarbamoyl!-2-(4-hydroxyphenyl)ethyl}-1H-indole-2-carboxamideEXAMPLE 28 (R)-4- (1-Carboxymethyl-1H-indole-2-carbonyl)amino!-4-(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl!butyric acid EXAMPLE 30(R)-{2-{1-{(2,6-Dimethoxy-4-methylphenyl)pentylcarbamoyl}-2-phenylethyl}carbamoyl!indol-1-yl}aceticacid EXAMPLE 31 (R)- 2-{1-{(2,6-Dimethoxy-4-methylphenyl)pentylcarbamoyl}-2-(4-hydroxyphenyl)ethyl!carbamoyl}indol-1-yl!aceticacid EXAMPLE 32 (R)- 2-{2-(Carbamoyl)-1-{(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl}ethyl!carbamoyl}indol-1-yl!aceticacid EXAMPLE 33 (R)- 2-{3-(Carbamoyl)-1-{(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl}propyl!carbamoyl}indol-1-yl!aceticacid EXAMPLE 44 Sodium (R)- 2-{1-{(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl}-2-(benzyloxy)ethyl!carbamoyl}indol-1-yl!acetateEXAMPLE 51 Sodium (R) -{2- {1-(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl!-2-(cyclohexyl)ethyl}carbamoyl!indol-1-yl}acetateEXAMPLE 81 (R)-{2- {1-(2,6-Dimethoxy-4-methylphenyl)pentylcarbamoyl!-2-(benzylthio)ethyl}carbamoyl!indol-1-yl}aceticacid EXAMPLE 82 (R)-{2- {1-(2,6-Dimethoxy-4-methylphenyl)pentylcarbamoyl!-3-(phenyl)propyl}carbamoyl!indol-1-yl}aceticacid EXAMPLE 85 2-{(6-Chloro-2,4-dimethoxy-5-methylphenyl)pentylcarbamoyl!methylcarbamoyl}indol-1-yl!aceticacid EXAMPLE 94 Sodium 2-{(5-chloro-2-methoxy-4-methylphenyl)pentylcarbamoyl!methylcarbamoyl}indol-1-yl!acetateEXAMPLE 103 2-{(2,5-Dimethoxy-4-methylphenyl)pentylcarbamoyl!methylcarbamoyl}indol-1-yl!aceticacid EXAMPLE 109 N-{(Isopentyl)(2,4,6-trimethoxyphenyl)carbamoyl!methyl}-1H-indol-2-carboxamideEXAMPLE 112 Sodium 2-{(benzyl)(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylcarbamoyl}indol-1-yl!acetateEXAMPLE 118 2-{(Cyclohexylmethyl)(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylcarbamoyl}indol-1-yl!aceticacid EXAMPLE 126 N-{(2,6-Dimethoxy-4-methylphenyl)pentylcarbamoyl!methyl}-2-naphthalenecarboxamideEXAMPLE 127 N-{(2,6-Dimethoxy-4-methylphenyl)pentylcarbamoyl!methyl}-3-quinolinecarboxamideEXAMPLE 137 8-{(2,6-Dimethoxy-4-methylphenyl)(3-methoxypropyl)carbamoyl!methylcarbamoyl}-5,6-dihydro-4H-pyrrolo3,2,1-ij!quinoline EXAMPLE 138 Methyl{2-(1-naphthyl)pentylcarbamoyl!methylcarbamoyl!indol-1-yl}acetate EXAMPLE139 {2- (1-Naphthyl)pentylcarbamoyl!methylcarbamoyl!indol-1-yl}aceticacid EXAMPLE 141 (R)- 2-{1-{N-(2,6-Dimethoxy-4-methylphenyl)-N-cyclohexyl}carbamoyl!ethylcarbamoyl}indol-1-yl!aceticacid EXAMPLE 155 (R)- 2-{ 1-{N-(2,6-Dimethoxy-4-methylphenyl)-N-cyclohexyl!carbamoyl}-2-(benzyloxy)ethyl!carbamoyl}indol-1-yl!aceticacid EXAMPLE 168 (R)- 2-{ 1-{N-(2,6-Dimethoxy-4-methylphenyl)-N-cyclohexyl!carbamoyl}-2-(cyclohexyl)ethyl!carbamoyl}indol-1-yl!aceticacid EXAMPLE 171 (R)- 2-{ 1-{N-(2,6-Dimethoxy-4-methylphenyl)-N-cyclohexylmethyl!carbamoyl}-2-(cyclohexyl)ethyl!carbamoyl}indol-1-yl!aceticacid EXAMPLE 172 (R)-{2- {1-(2,6-Dimethoxy-4-methylphenyl)butylcarbamoyl!-2-(benzyloxy)ethyl}carbamoyl!indol-1-yl}aceticacid EXAMPLE 192 (R)-{2- N-{1-(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl!-5-(cinnamoylamino)pentyl}carbamoyl!indol-1-yl}aceticacid

The compounds according to the invention are prepared according to thefollowing reaction scheme: ##STR6##

According to another of its aspects, the present invention relates to aprocess for the preparation of the compounds of formula (I)characterized in that an amine of formula: ##STR7## in which Ar andR_(I) are as defined above, is treated with an N-protected amino acid offormula: ##STR8## in which R_(II) is as defined for (I) and in which, ifappropriate, the reactive groups of R_(II) have been protected, in orderto lead to a compound of formula: ##STR9## in which R_(I), Ar and R_(II)are as defined above, in order to lead to a compound (I) according tothe invention or one of its salts.

The starting compounds of formulae (II) are either commerciallyavailable or prepared according to known methods, for example:

for 2,6-dimethoxy-4-methylaniline, according to an adaptation of theprocess described by Mori S. et al. Tet. Lett., 1984, 25, 429;

for 2,4-dimethoxy-5-methylaniline, according to Sargent M. V., J. Chem.Soc. Perkins Trans I, 1982, 1095;

for 2,4,6-trimethoxyaniline, according to EP-A-088849;

for 2,5-dimethoxy-4-methylaniline, according to Shaikh Y. A., J.Heterocyclic Chem., 1977, 14, 1049;

for 2,6-dimethoxy-4-trifluoromethylaniline, according to an adaptationof the process described by Mori S. et al., Tet. Lett., 1984, 25, 429from 1,5-dimethoxy-3-trifluoromethylbenzene prepared according toRobertson A. et al., J. Chem. Soc., 1951, 2013;

for 4-chloro-2,6-dimethoxyaniline, according to Hodgson H. et al., J.Chem. Soc., 1934, 1433;

for 1-amino-2,6-dimethoxy-4-methylpyrimidine, according to Urban R. etal., Holv. Chim. Acta, 1958, 41, 1806;

for the compound of formula: ##STR10## according to EP-0,572,235.

When R_(I) is other than a cycloalkyl, the anilines of formula (II) orthe compounds of formula (IV) in which Ar is as defined for (I) can beprepared according to known methods according to the following Scheme 2:##STR11## either by acylation of a compound of formula:

    Ar--NH.sub.2                                               (VI)

in which Ar is as defined for (I), with an acid halide of formulaR'--CO--X, in which X represents a chlorine or bromine atom and R' issuch that R'--CH₂ -- represents R_(I) as defined for (I), or with one ofits activated esters, in the presence of an organic base such astriethylamine or N-ethylmorpholine, in organic solvents such as diethylether, dichloromethane, chloroform, dimethylformamide ortetrahydrofuran, in order to lead to a compound of formula: ##STR12## inwhich R' and Ar as defined above, in order subsequently to reduce itwith an alkali metal hydride such as lithium aluminium hydride, in aninert organic solvent such as diethyl or diisopropyl ether ortetrahydrofuran, in order to lead to a compound of formula (II),

or by coupling of the compound (VI) with an N-protected amino acid,which has been activated beforehand, of formula (III), in order to leadto a compound of formula: ##STR13## in which R_(II) and Ar are asdefined for (I), which is then N-alkylated, after generation of theanion with a strong base, in order to obtain a compound of formula:##STR14## in which R_(I), R_(II) and Ar are as defined for (I), thiscompound then being treated in anhydrous acidic medium in order toprovide a compound (V) in the salt form of formula: ##STR15## which isthen acylated with an acid of formula R_(III) COOH, which has beenactivated beforehand, in order to lead to a compound (I) according tothe invention or one of its optional salts.

When R_(I) represents a cycloalkyl, the anilines of formula (II) arenovel and can be prepared independently according to one of Schemes 3, 4or 5 below. ##STR16##

The coupling reaction of the aniline (A), in which Ar is as defined for(I), with the cycloalkanone leads to the Schiff base (B) which is thenreduced according to the usual conditions, for example by reacting witha sodium borohydride in ethanol or by reacting with formic acid atreflux. ##STR17##

This synthesis is an adaptation of the process described by J. T. Pinkeyet al., J. Chem. Soc. Perkin Trans I, 1990, 715 for the preparation ofthe compounds (D) and (E) and of the process described by D. H. R.Barton et al., Tet. Lett., 1987, 28(27), 3111. ##STR18##

The amino acids used are activated by the coupling reagents commonlyused in peptide chemistry, for example, in the case of racemic aminoacids or amino acids which do not have an asymmetric centre: BOP/NEt₃,BOP-Cl/NEt₃, DCC/HOBT/NEt₃ or mixed anhydride with ClCOOiBu in thepresence of triethylamine and, in the case of R or S enantiomers ofamino acids, in the presence of BOP/N-ethylmorpholine or Boc₂O/pyridine.

The anions of the compounds (VIII) are generated by strong bases suchas, for example, sodium hydride or potassium tert-butoxide in an aproticanhydrous solvent, such as tetrahydrofuran.

The compounds (V) are obtained from the acetanilides (IV) in anhydrousacidic medium such as trifluoroacetic acid in dichloromethane or gaseoushydrochloric acid in solution in ethyl acetate, for example.

The compounds (V) are then isolated in the hydrochloride ortrifluoroacetate form, for example.

The compounds (I) are obtained by the conventional methods for peptidecoupling between the compounds (V) and the acids R_(III) COOH, whichhave been activated beforehand in the form of an acid halide, in theform of a mixed anhydride, with, for example, ClCOOiBu, or in the formof an activated ester with BOP/NEt₃, BOP/N-ethylmorpholine, BOP-Cl/NEt₃,DCC/HOBT/NEt₃, Boc₂ O/pyridine, according to methods which are wellknown to a person skilled in the art.

The optional salts of the compounds of formula (I) with organic orinorganic acids or bases are prepared in the usual way by introducingthe acid, or the base, into a solution of the compound of formula (I).

The salt is isolated, depending on its solubility characteristics, afterevaporation of the solvent or addition of a nonsolvent.

The compounds of formula (V) in which R_(I), Ar and R_(II) are asdefined above for (I) are novel and constitute one of the subjects ofthe invention.

Another subject of the invention, according to another of its aspects,is pharmaceutical compositions comprising the above compounds (I).

More generally, the compounds of formula (I) have formed the subject ofin vitro binding studies relating to CCK receptors.

A study of the agonist effect of the compounds on the secretion ofamylase was carried out as follows. Pancreas acini are obtained byenzymatic digestion (collagenase) of the pancreas of a rat which hasfasted for 18 hours. Aliquots (485 μl) are incubated at 37° C. for 30minutes in the presence of increasing concentrations of agonistaccording to Jensen et al., J. Biol. Chem., 1982, 257 (10), 5554.Incubation is halted by centrifuging for 15 seconds. The supernatant isstored in an ice bath in order to measure the amylase level according tothe technique of Ceska et al., Clin. Chim. Acta., 1969, 26, 437 (reagentPhadebas®: amylase test marketed by Pharmacia Diagnostic). The compoundsto be tested are dissolved in dimethyl sulphoxide and then in anincubation buffer.

The compounds of formula (I) behave as agonists of CCK-A receptors withEC₅₀ values (effective concentration inducing 50% of the amylasesecretion compared with a maximum effect produced in the presence ofCCK) of about 10⁻⁷ to 10⁻⁹ M.

A study of the agonist effect of the compounds on the contraction of thegall bladder was carried out as follows. Female albino Swiss CD1 mice(20-25 g) are fasted from solid food for 24 hours. On the day of theexperiment, the products (in suspension in a 1% carboxymethyl celluloseor 0.6% methyl cellulose solution) or the corresponding vehicle areadministered orally. The mice are sacrificed by cervical dislocation onehour after administration of the products and the gall bladders areremoved and weighed. The results are expressed in mg/kg of bodyweight(Europ. J. Pharmacol., 1993, 232, 13-19).

The compounds of formula (I) completely contract the gall bladder, likeCCK itself, and therefore behave as agonists of CCK-A receptors. Some ofthem have ED₅₀ values (effective dose inducing 50% of the decrease inweight of the bladders observed with CCK) of less than 3 mg/kg orally.

A study of the agonist effect of the compounds on gastric dumping wascarried out as follows. Female albino Swiss CD1 mice (20-25 g) arefasted from solid food for 18 hours. On the day of the experiment, theproducts (in suspension in a 1% carboxymethyl cellulose or 0.6% methylcellulose solution) or the corresponding vehicle are administeredintraperitoneally 30 minutes before administration of a charcoal meal(0.3 ml per mouse of a suspension, in water, of 10% of charcoal powder,5% of gum arabic and 1% of carboxymethyl cellulose). The mice aresacrificed 5 minutes later by cervical dislocation and gastric dumpingis defined as the presence of charcoal in the intestine beyond thepyloric sphincter (Europ. J. Pharmacol., 1993, 232, 13-19).

The compounds of formula (I) completely block gastric dumping, like CCKitself, and therefore behave as agonists of CCK receptors. Some of themhave ED₅₀ values (effective dose inducing 50% of the effect of CCK) ofless than 1 mg/kg intraperitoneally.

A study of the CCK agonist effect of the compounds on food consumptionwas carried out as follows. Male Sprague Dawley (Charles River, France)rats (200-240 g) are isolated 10 days before the experiment and aresubjected, each day, successively to 18 hours of fasting and 6 hours offeeding: food is available from 1000 hours to 1600 hours and water isavailable ad libitum. On the day of the experiment, the products (insuspension in a 0.6% methyl cellulose solution) or the vehicle areadministered intraperitoneally.

Thirty minutes after the treatment (at 10 hours), a known amount of foodis introduced into the cage: food consumption is measured 1 hour and 3hours later.

The compounds of formula (I) decrease food uptake and therefore behaveas agonists of CCK-A receptors (Gibbs J. et al., J. Comp. Physiol.Psychol., 1973, 488-495).

Some of them are active at the oral dose of 3 mg/kg, at which dose theyreduce food consumption by 30 to 40% with respect to a control animal.

Consequently, the compounds of formula (I) are used as agonists of CCK-Areceptors for the preparation of medicines intended for combatingdiseases whose treatment requires stimulation by total or partialagonism of cholecystokinin receptors, more particularly for themanufacture of medicines intended for the treatment of certain disordersof food behaviour, of obesity, of diabetes, of disorders of emotional,sexual and memory behaviour, of psychoses and in particularschizophrenia, of Parkinson's disease, of tardive dyskinesia and ofvarious disorders of the gastrointestinal sphere.

The compounds of formula (I) have little toxicity; their toxicity iscompatible with their use as medicines for the treatment of the abovedisorders and diseases.

The compounds of formula (I) can be formulated in pharmaceuticalcompositions for administration to mammals, including man, for thetreatment of the abovesaid diseases.

The compounds of formula (I) above and their pharmaceutically acceptablesalts can be used at daily doses of 0.01 to 100 mg per kilo of bodyweight of the mammal to be treated, preferably at daily doses of 0.1 to50 mg/kg.

In man, the dose can preferably vary from 0.5 to 4,000 mg per day, moreparticularly from 2.5 to 1,000 mg, according to the age of the subjectto be treated or the type of treatment: prophylactic or curative.

In the pharmaceutical compositions of the present invention, the activeprinciple is generally formulated in dosage units containing from 0.5 to1,000 mg, advantageously from 1 to 500 mg and preferably from 2 to 200mg of the said active principle per dosage unit.

Another subject of the present invention is therefore pharmaceuticalcompositions which contain, as active principle, one of the abovecompounds. These compositions are prepared so as to be able to beadministered by the digestive or parental route.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, transdermal, localor rectal administration, the active ingredient can be administered inunit administration forms, as a mixture with conventional pharmaceuticalvehicles, to animals and to man. The appropriate unit administrationforms comprise oral forms, such as tablets, gelatin capsules, powders,granules and oral solutions or suspensions, sublingual and buccaladministration forms, subcutaneous, intramuscular, intravenous,intranasal or intraocular administration forms and rectal administrationforms.

When a solid composition is prepared in the form of tablets, the mainactive ingredient is mixed with a pharmaceutical vehicle, such asgelatin, starch, lactose, magnesium stearate, talc, gum arabic orsimilar. The tablets can be coated with sucrose or other appropriatematerials or alternatively they can be treated so that they have aprolonged or delayed activity and so that they continuously release apredetermined amount of active principle.

A gelatin capsule preparation is obtained by mixing the activeingredient with a diluent and by pouring the mixture obtained into softor hard gelatin capsules.

A preparation in the syrup or elixir form can contain the activeingredient jointly with a sweetener, preferably a calorie-free one,methylparaben and propylparaben as antiseptic, as well as an agentgiving taste and an appropriate dye.

Water-dispersible granules or powders can contain the active ingredientas a mixture with dispersing agents or wetting agents or suspendingagents, such as polyvinylpyrrolidone, as well as with sweeteners ortaste correctors.

For rectal administration, recourse is made of suppositories which areprepared with binders which melt at rectal temperature, for examplecocoa butter or polyethylene glycols.

For parental, intranasal or intraocular administration, use is made ofaqueous suspensions, isotonic saline solutions or sterile and injectablesolutions which contain pharmacologically compatible dispersing agentsand/or wetting agents, for example propylene glycol or butylene glycol.

The active principle can also be formulated in the form ofmicrocapsules, optionally with one or a number of vehicles or additives.

The active principle can also be presented in the form of a complex witha cyclodextrin, for example α-, β- or γ-cyclodextrin,2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.

In what follows, a description is given of EXAMPLES of theimplementation of the invention, as well as of the preparations of somesynthetic intermediates of formula (II), (IV), (V), (VII) and (VIII).The melting points indicated were determined in capillary tubes.

PREPARATION I

Compound 1--Intermediate of formula (II) ##STR19##

Stage 1

4.2 g of 2,6-dimethoxy-4-methylaniline are dissolved in 50 ml oftoluene, 2.45 g of cyclohexanone are then added and the reaction mixtureis heated at reflux for 18 hours. The water which is formed is removedas it is formed in the reaction mixture using a Dean and Starkapparatus. The toluene is evaporated and the oilyN-cyclohexylidene-2,6-dimethoxy-4-methylaniline residue obtained is usedwithout addition of purification in the following stage.

Stage 2

a) Reduction of the alkylidene with formic acid:

The alkylidene obtained above is dissolved in 50 ml of toluene and 1.15g of formic acid are added thereto dropwise, under an inert atmosphere.The reaction mixture is heated at reflux under an inert atmosphere for 4hours. After cooling, the reaction mixture is poured in 100 ml of a 2Naqueous sodium hydroxide solution and then extraction is carried outwith ethyl acetate. The organic extracts are dried over anhydrous sodiumsulphate and evaporated to dryness. The residual oil is purified byflash chromatography on a colum of silica gel, eluent:dichloromethane/methanol 98/2 (v/v), to provide an oil, Yield: 80%. Theoil is converted to the hydrochloride by addition of a 5N solution ofhydrogen chloride gas in diethyl ether, white crystals, M.p.=199° C.(hydrochloride).

b) Reduction of the alkylidene with NaBH₄

The alkylidene obtained in Stage 1 is dissolved in 50 ml of ethanol and0.95 g of sodium borohydride is added thereto in small portions, underan inert atmosphere, and the reaction mixture is left at roomtemperature for 2 hours. 20 ml of acetone are added to the reactionmixture, which is evaporated to dryness. The residue is taken up inwater and the aqueous phase is extracted with dichloromethane. Theorganic extracts are dried over anhydrous sodium sulphate and evaporatedto dryness. The oily residue is chromatographed on a column of silicagel, eluent: dichloromethane/methanol 98/2 (v/v). The oil obtained isconverted to N-cyclohexyl-2,6-dimethoxy-4-methylaniline hydrochloride,white crystals, M.p.=199° C. (hydrochloride), Yield: 85%.

Compound 2--Intermediate of formula (II) ##STR20##

Stage 1

300 ml of a solution (1.6M) of butyllithium in hexane are added dropwiseat room temperature to a solution of 73 g of 3,5-dimethoxytoluene in 450ml of diethyl ether. The reaction mixture is heated at reflux for 3hours under an inert atmosphere, the reaction mixture is then cooled to-60° C. and 99.7 g of methyl borate are added dropwise over 60 minutes.The reaction mixture is left at -60° C. for 3 hours and left to returnto room temperature. The reaction mixture is stirred at room temperaturefor 16 hours, 6N hydrochloric acid is then added to the reaction mixture(pH=1) and the reaction mixture is left to separate by settling. Theorganic phase is recovered. The aqueous phase is extracted with diethylether. The combined organic phases are dried over anhydrous sodiumsulphate. Evaporation of the solvent leaves a yellow oil whichcrystallizes by cooling to 0° C. After drying, white crystals of2,6-dimethoxy-4-methylphenylboronic acid are recovered, M.p.=108° C.,Yield 80%.

45.4 g of lead tetraacetate and 3.2 g of mercuric acetate are suspendedin 150 ml of anhydrous chloroform and the mixture is heated to 40° C.under an argon atmosphere. A solution of 20 g of2,6-dimethoxy-4-methylphenylboronic acid (prepared above) in 100 ml ofchloroform is added dropwise to the reaction mixture at 40° C. Thereaction mixture is left for 75 minutes at 40° C. and is then left toreturn to room temperature while stirring well. The reaction mixture isstirred at room temperature for 18 hours and is then diluted with 800 mlof dichloromethane. The solution is filtered over a bed of celite andthe solvent is then evaporated to dryness in order to obtain yellowcrystals of 2,6-dimethoxy-4-methylphenyllead triacetate, M.p.=172° C.,Yield: 90%.

Stage 2

10.56 g of cyclooctylamine are dissolved in 500 ml of anhydrousdichloromethane and 1.5 g of cupric acetate are added thereto. Asolution of 44.2 g of 2,6-dimethoxy-4-methylphenyllead triacetate,prepared above, in 250 ml of anhydrous dichloromethane is added dropwiseto the reaction mixture under an inert atmosphere. The reaction mixtureis left at room temperature for 18 hours, the heterogeneous mixture isthen filtered over a bed of celite and the filtrate is concentrated to450 ml. The organic phase is washed with water (3 times). The organicphase is extracted with 3×300 ml of 1N hydrochloric acid. The acidicaqeuous phase is basified with a 2N aqueous sodium hydroxide solution(pH=11). The alkaline aqeuous phase is extracted with dichloromethaneand the organic extracts are dried over anhydrous sodium sulphate.Evaporation leaves an oil which is purified by flash chromatography on acolumn of silica gel, eluent:dichloromethane/methanol:99/1 (v/v) inorder to obtain N-cyclooctyl-2,6-dimethoxy-4-methylaniline in the formof an oil. Yield 52%.

Compound 3--Intermediate of formula (II) ##STR21##

2.1 g of 2,6-dimethoxy-4-methylaniline are dissolved in 10 ml oftoluene, 0.5 ml of formic acid is then added to this solution and themixture is heated to gentle reflux, under inert atmosphere, and 0.93 gof 2-adamantanone, dissolved in 10 ml of toluene, is added dropwise atthis temperature. The reaction mixture is heated at reflux for 48 hours,is then evaporated to dryness and the residue is taken up in 30 ml of 2Nhydrochloric acid. The insoluble white crystals are filtered anddiscarded. The acidic filtrate is extracted with dichloromethane. Theorganic extracts are washed with a 5% aqueous sodium bicarbonatesolution and then with water and the organic phases are then dried overanhydrous sodium sulphate. Evaporation leaves a colourless residue whichis purified by flash chromatography on a column of silica gel, eluent:toluene/ethyl acetate 7/3 (v/v) in order to obtainN-(2-adamantyl)-2,6-dimethoxy-4-methylaniline; M.p.=100° C., Yield 52%.

Compound 4--Intermediate of formula (II) ##STR22##

Stage 1

3.4 g of 2,6-dimethoxy-4-methylaniline are dissolved in 40 ml oftoluene. 1.03 g of formic acid are added to the solution and thereaction mixture is heated at reflux, under an inert atmosphere, for 24hours. Evaporation is carried out to dryness and the residue is taken upin 40 ml of 2N hydrochloric acid, stirring is then carried out for 30minutes at room temperature and the precipitate is filtered and dried.3.6 g of white crystals of N-formyl-2,6-dimethoxy-4-methylaniline areobtained, M.p.=132° C., Yield: 90%.

Stage 2

6 g of N-formyl-2,6-dimethoxy-4-methylaniline are suspended in 100 ml oftetrahydrofuran and then 33 ml of a 1M solution of lithium aluminiumhydride in tetrahydrofuran are added dropwise under an inert atmosphere.The reaction mixture become homogeneous. The reaction mixture is left atroom temperature for 2 hours and then, after cooling to 0° C., 1 ml ofwater, then 1 ml of a 15% aqueous sodium hydroxide solution and then 3ml of water are successively added dropwise to the reaction mixture. Thewhole mixture is diluted with 100 ml of ethyl acetate and theprecipitate is filtered. The filtrate, evaporated to dryness, leaves anoily residue which is purified by flash chromatography on a column ofsilica gel, eluent: toluene/ethyl acetate 8/2 (v/v) in order to obtainN-methyl-2,6-dimethoxy-4-methylaniline in the form of an oil, Yield:85%.

PREPARATION II

Compound 5--Intermediate of formula (VII) ##STR23##

8.2 g of 2,6-dimethoxy-4-methylaniline are dissolved in 100 ml ofdiethyl ether at 0° C. under an inert atmosphere, 5.96 g oftriethylamine are added to the reaction mixture and then 6.51 g ofisovaleryl chloride are added dropwise, while maintaining thetemperature at 0° C. The mixture is left at room temperature for 30minutes and is then poured into 250 ml of water. The aqueous phase isextracted with ethyl acetate after separation by settling of theethereal phase. The organic phases are combined and washed with water,then dried over anhydrous sodium sulphate and evaporated to dryness. Thewhite crystals of N-(2,6-dimethoxy-4-methylphenyl)isovaleramide obtainedare washed with diisopropyl ether; M.p.=139° C., Yield: 92%.

By carrying out the preparations according to PREPARATION II, theintermediate compounds 6 to 25 described below in TABLE A are prepared.

                  TABLE A                                                         ______________________________________                                        Intermediates of formula (VII)                                                 ##STR24##                                                                    Com-                                                                          pound R'            X.sub.1 X.sub.2                                                                             X.sub.3                                                                             M.p.; °C.                      ______________________________________                                         6    (CH.sub.2).sub.3 CH.sub.3                                                                   OCH.sub.3                                                                             OCH.sub.3                                                                           H      72                                    7    (CH.sub.2).sub.3 CH.sub.3                                                                   CH.sub.3                                                                              OCH.sub.3                                                                           H     101                                    8    (CH.sub.2).sub.3 CH.sub.3                                                                   OCH.sub.3                                                                             CH.sub.3                                                                            Cl    138                                    9    (CH.sub.2).sub.3 CH.sub.3                                                                   Cl      CH.sub.3                                                                            H      90                                   10    (CH.sub.2).sub.3 CH.sub.3                                                                   Cl      OCH.sub.3                                                                           H     113                                   11    (CH.sub.2).sub.3 CH.sub.3                                                                   CH.sub.3                                                                              Cl    H      80                                   12    (CH.sub.2).sub.5 CH.sub.3                                                                   CH.sub.3                                                                              H     OCH.sub.3                                                                            94                                   13    CH.sub.2CH(CH.sub.3).sub.2                                                                  OCH.sub.3                                                                             H     OCH.sub.3                                                                           142                                   14                                                                                   ##STR25##    CH.sub.3                                                                              H     OCH.sub.3                                                                           210                                   15    (CH.sub.2).sub.2 OCH.sub.3                                                                  CH.sub.3                                                                              H     OCH.sub.3                                                                           116                                   16                                                                                   ##STR26##    CH.sub.3                                                                              H     OCH.sub.3                                                                           110                                   17                                                                                   ##STR27##    CH.sub.3                                                                              H     OCH.sub.3                                                                           126                                   18    (CH.sub.2).sub.3 CH.sub.3                                                                   (VII): Ar =     113                                                           1-naphthyl                                                19    (CH.sub.2).sub.3 CH.sub.3                                                                   OCH.sub.3                                                                             CH.sub.3                                                                            H      91                                   20    (CH.sub.2).sub.3 CH.sub.3                                                                   OCH.sub.3                                                                             H     OCH.sub.3                                                                           125                                   21    (CH.sub.2).sub.2 CH.sub.3                                                                   CH.sub.3                                                                              H     OCH.sub.3                                                                           123                                   22                                                                                   ##STR28##    CH.sub.3                                                                              H     OCH.sub.3                                                                           180                                   23    CH.sub.3      CH.sub.3                                                                              H     OCH.sub.3                                                                           156                                   24                                                                                   ##STR29##    CH.sub.3                                                                              H     OCH.sub.3                                                                           178                                   25    H             CH.sub.3                                                                              H     OCH.sub.3                                                                           132                                   ______________________________________                                    

PREPARATION III

Compound 26--Intermediate of formula (II) ##STR30##

8.5 g of the anilide (compound 5) prepared above are dissolved in 160 mlof dry tetrahydrofuran, which are cooled to 0° C. 34 ml of a 1M solutionof lithium aluminium hydride in tetrahydrofuran are added dropwise, thereaction mixture is then left to return to room temperature and isheated at reflux for 2 h 30. It is left to return to room temperatureand then cooled to 0° C. 2.5 ml of ice-cold water, 7 ml of a 6N aqueoussodium hydroxide solution and then 2.5 ml of water are successivelyadded to the reaction mixture at 0° C.; the insoluble material isseparated by filtration and is washed on a Buchner filter with ethylacetate. The filtrate is washed with salted water, dried over anhydroussodium sulphate and evaporated under vacuum. A yellow oil is recoveredwhich is purified by flash chromatography on a column of silica gel,eluent: dichloromethane/diethyl ether 98/2 (v/v) in order to provideN-isopentyl-2,6-dimethoxy-4-methylaniline, in the form of oil. Yield:89%.

By carrying out the preparations according to PREPARATIONS I and III,the intermediates 27 to 45 described below in TABLE B are prepared.

                  TABLE B                                                         ______________________________________                                        Intermediates of formula (II)                                                  ##STR31##                                                                                                              M.p.;                               Com-                                      °C.                          pound R.sub.I         X.sub.1 X.sub.2                                                                             X.sub.3                                                                             salt                                ______________________________________                                        27    (CH.sub.2).sub.4 CH.sub.3                                                                     CH.sub.3                                                                              H     OCH.sub.3                                                                           217,                                                                          HCl                                 28    (CH.sub.2).sub.4 CH.sub.3                                                                     OCH.sub.3                                                                             OCH.sub.3                                                                           H     oil                                 29    (CH.sub.2).sub.4 CH.sub.3                                                                     CH.sub.3                                                                              OCH.sub.3                                                                           H     38                                  30    (CH.sub.2).sub.4 CH.sub.3                                                                     OCH.sub.3                                                                             CH.sub.3                                                                            Cl    oil                                 31    (CH.sub.2).sub.4 CH.sub.3                                                                     Cl      CH.sub.3                                                                            H     oil                                 32    (CH.sub.2).sub.4 CH.sub.3                                                                     Cl      OCH.sub.3                                                                           H     40                                  33    (CH.sub.2).sub.4 CH.sub.3                                                                     CH.sub.3                                                                              Cl    H     64                                  34    (CH.sub.2).sub.6CH.sub.3                                                                      CH.sub.3                                                                              H     OCH.sub.3                                                                           oil                                 35    (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                           OCH.sub.3                                                                             H     OCH.sub.3                                                                           180,                                                                          HCl                                 36                                                                                   ##STR32##      CH.sub.3                                                                              H     OCH.sub.3                                                                           oil                                 37    (CH.sub.2).sub.3 OCH.sub.3                                                                    CH.sub.3                                                                              H     OCH.sub.3                                                                           oil                                 38                                                                                   ##STR33##      CH.sub.3                                                                              H     OCH.sub.3                                                                           oil                                 39    (CH.sub.2).sub.4 CH.sub.3                                                                     (II): Ar =      oil                                                           1-naphthyl                                              40    (CH.sub.2).sub.4 CH.sub.3                                                                     OCH.sub.3                                                                             CH.sub.3                                                                            H     oil                                 41    (CH.sub.2).sub.4 CH.sub.3                                                                     OCH.sub.3                                                                             H     OCH.sub.3                                                                           oil                                 42    (CH.sub.2).sub.3 CH.sub.3                                                                     CH.sub.3                                                                              H     OCH.sub.3                                                                           oil                                 43                                                                                   ##STR34##      CH.sub.3                                                                              H     OCH.sub.3                                                                           oil                                 44                                                                                   ##STR35##      CH.sub.3                                                                              H     OCH.sub.3                                                                           oil                                 45    CH.sub.3        CH.sub.3                                                                              H     OCH.sub.3                                                                           oil                                 ______________________________________                                    

PREPARATION IV

Compound 46--Intermediate of formula (IV) ##STR36##

Synthesis with a non-chiral amino acid.

5.5 g of the aniline (compound 26) prepared above are dissolved in 60 mlof dimethylformamide. 10.8 g of BOP, 4.26 g of N-Boc-glycine and then,dropwise, 4.69 g of triethylamine are successively added to the reactionmixture and the reaction mixture is left under an inert atmosphere, atroom temperature, for 20 hours. The reaction mixture is poured into 200ml of cold water and the aqueous phase is extracted with ethyl acetate.The organic phase is washed with water and dried over anhydrous sodiumsulphate. Evaporation of the solvent leaves white crystals which arepurified by flash chromatography on a column of silica gel, eluent:dichloromethane/diethyl ether 95/5 (v/v) in order to obtain whitecrystals of N-tert-butyloxycarbonyl-(2,6-dimethoxy-4-methylphenyl)(isopentyl)carbamoyl!methylamine;M.p.=132° C.; Yield: 91%.

PREPARATION V

Compound 47--Intermediate of formula (VIII) ##STR37##

Synthesis with a non-chiral amino acid.

6.6 g of N-Boc-glycine and 15.6 g of BOP are successively added to 100ml of dimethylformamide and then, at 0° C., 14 ml of triethylamine areadded dropwise. The mixture is left for 20 minutes at 0° C. and 6.7 g of2,6-dimethoxy-4-methylaniline hydrochloride are then added portionwise.The reaction mixture is left at room temperature for 15 hours. 400 ml ofethyl acetate are added to the reaction mixture and the organic phase issuccessively washed with 3×200 ml of water, with a 1N aqueous sodiumhydroxide solution and then with water. The organic phase is dried overanhydrous sodium sulphate. Evaporation of the solvent leaves asemi-crystalline residue which is solidified in diisopropyl ether toprovide N-tert-butyloxycarbonyl-(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylamine, in the form ofwhite crystals; M.p.=146° C.; Yield: 96%.

PREPARATION VI

Compound 48--Intermediate of formula ##STR38##

Synthesis with a chiral amino acid.

3.2 g of N-pentyl-2,6-dimethoxy-4-methylaniline (compound 27)(II) aredissolved in 50 ml of dimethylformamide and 5 g of the β-O-benzyl esterof N-Boc-aspartic acid, 7.2 g of BOP and then, dropwise, 1.6 g ofN-ethylmorpholine are successively added at 0° C. and the reactionmixture is left at room temperature for 19 hours. 200 ml of ethylacetate are then added and the organic phase is successively washed with2×200 ml of water, 100 ml of a 0.1N aqueous sodium hydroxide solution,100 ml of a 0.1N aqueous hydrochloric acid solution and two times 200 mlof water.

The organic phase is dried over anhydrous sodium sulphate and evaporatedto dryness. The orange-coloured oil obtained is purified by filtrationover a bed of silica, eluent: dichloromethane, in order to obtainbenzyl3-(N-tert-butyloxycarbonyl)amino-3-{(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl}propionatein the form of an oil; Yield: 98%.

PREPARATION VII

Compound 49--Intermediate of formula (IV) ##STR39##

3.99 g of N-tert-butyloxycarbonyl-(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylamine (compound 47) aredissolved in 50 ml of dimethylformamide and 0.5 g of sodium hydride, asa 60% suspension in oil, is added portionwise at 0° C. The reactionmixture is stirred at room temperature for 30 minutes and then 2.16 g ofbenzyl bromide, in solution in 30 ml of dimethylformamide, are addeddropwise to the reaction mixture. The reaction mixture is left at roomtemperature for 2 hours and then 300 ml of ethyl acetate are added. Theorganic phase is washed with water and dried over anhydrous sodiumsulphate. Evaporation of the solvent leaves a semi-crystalline residuewhich is solidified in diisopropyl ether in order to obtain:N-tert-butyloxycarbonyl-benzyl(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylamine in the form ofwhite crystals, M.p.=163° C.; Yield: 85%.

By carrying out the preparations according to PREPARATIONS IV, VI andVII, the intermediate compounds 50 to 99 described in TABLE C below areprepared.

                                      TABLE C                                     __________________________________________________________________________    Intermediates of formula (IV)                                                  ##STR40##                                                                    Com-                                                                          pound           R.sub.II and             M.p.;                                No. R.sub.I     configuration                                                                              X.sub.1                                                                           X.sub.2                                                                           X.sub.3                                                                           °C.                           __________________________________________________________________________    50  (CH.sub.2).sub.4 CH.sub.3                                                                 H            CH.sub.3                                                                          H   OCH.sub.3                                                                         124                                  51  (CH.sub.2).sub.4 CH.sub.3                                                                 H            OCH.sub.3                                                                         CH.sub.3                                                                          Cl  oil                                  52  (CH.sub.2).sub.4 CH.sub.3                                                                 H            OCH.sub.3                                                                         OCH.sub.3                                                                         H   174                                  53  (CH.sub.2).sub.4 CH.sub.3                                                                 H            Cl  CH.sub.3                                                                          H   oil                                  54  (CH.sub.2).sub.4 CH.sub.3                                                                 H            Cl  OCH.sub.3                                                                         H    84                                  55  (CH.sub.2).sub.4 CH.sub.3                                                                 H            CH.sub.3                                                                          OCH.sub.3                                                                         H   122                                  56  (CH.sub.2).sub.4 CH.sub.3                                                                 CH.sub.2 CH.sub.2 CONH.sub.2 (R)                                                           CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  57  (CH.sub.2).sub.4 CH.sub.3                                                                 CH.sub.2 CONH.sub.2 (R)                                                                    CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  58  (CH.sub.2).sub.4 CH.sub.3                                                                 CH.sub.2 (R) CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  59  (CH.sub.2).sub.6 CH.sub.3                                                                 H            CH.sub.3                                                                          H   OCH.sub.3                                                                         108                                  60  (CH.sub.2).sub.3 OCH.sub.3                                                                H            CH.sub.3                                                                          H   OCH.sub.3                                                                         135                                  61  (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                       H            OCH.sub.3                                                                         H   OCH.sub.3                                                                         oil                                  62                                                                                 ##STR41##  H            CH.sub.3                                                                          H   OCH.sub.3                                                                         191                                  63                                                                                 ##STR42##  H            CH.sub.3                                                                          H   OCH.sub.3                                                                         170                                  64  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR43##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  65  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR44##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  66  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR45##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  67  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR46##   CH.sub.3                                                                          H   OCH.sub.3                                                                         159                                  68  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR47##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  69  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR48##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  70  (CH.sub.2).sub.4 CH.sub.3                                                                 H            Ar = 1-naphthyl                                                                           oil                                  71                                                                                 ##STR49##  CH.sub.3 (R) CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  72  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR50##   OCH.sub.3                                                                         CH.sub.3                                                                          Cl  oil                                  73  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR51##   OCH.sub.3                                                                         CH.sub.3                                                                          H   oil                                  74                                                                                 ##STR52##                                                                                 ##STR53##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  75  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR54##   CH.sub.3                                                                          Cl  H   oil                                  76                                                                                 ##STR55##                                                                                 ##STR56##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  77                                                                                 ##STR57##                                                                                 ##STR58##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  78  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR59##   Cl  CH.sub.3                                                                          H   oil                                  79                                                                                 ##STR60##                                                                                 ##STR61##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  80  (CH.sub.2).sub.3 CH.sub.3                                                                  ##STR62##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  81  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR63##   OCH.sub.3                                                                         H   OCH.sub.3                                                                         oil                                  82                                                                                 ##STR64##                                                                                 ##STR65##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  83                                                                                 ##STR66##                                                                                 ##STR67##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  84  (CH.sub.2).sub.4 CH.sub.3                                                                 CH.sub.3 (S) CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  85  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR68##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  86  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR69##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  87  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR70##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  88  (CH.sub.2).sub.4 CH.sub.3                                                                 CH(CH.sub.3).sub.2 (R)                                                                     CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  89  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR71##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  90  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR72##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  91  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR73##   Cl  OCH.sub.3                                                                         H   oil                                  92  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR74##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  93  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR75##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  94                                                                                 ##STR76##                                                                                 ##STR77##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  95  CH.sub.2 CH.sub.3                                                                          ##STR78##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  96                                                                                 ##STR79##                                                                                 ##STR80##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  97  CH.sub.3                                                                                   ##STR81##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  98                                                                                 ##STR82##                                                                                 ##STR83##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  99                                                                                 ##STR84##                                                                                 ##STR85##   CH.sub.3                                                                          H   OCH.sub.3                                                                         oil                                  __________________________________________________________________________

PREPARATION VIII

Compound 100--Intermediate of formula (V) ##STR86##

7.8 g of N-BOC-substituted anilide (IV) (compound 46) prepared aboveaccording to PREPARATION IV are dissolved in 80 ml of ethyl acetate andcooling is carried out to 0° C. 50 ml of a saturated solution of gaseoushydrochloric acid in ethyl acetate are added to the reaction mixture andthe reaction mixture is then left to return to room temperature over 2hours. The ethyl acetate is evaporated to dryness and thesemi-crystalline residue is taken up in diethyl ether. The whitecrystals obtained are filtered and washed with diethyl ether in order toprovide white crystals of(2,6-dimethoxy-4-methylphenyl)(isopentyl)carbamoyl!methylaminehydrochloride; M.p.=214° C.; Yield: 96%.

By carrying out the preparations according to PREPARATION VIII, theintermediate compounds 101 to 151 described in TABLE D below areprepared.

                                      TABLE D                                     __________________________________________________________________________    Intermediates of formula (V)                                                   ##STR87##                                                                                                                    M.p.; °C.              Compound            R.sub.II and                 α!.sub.D.sup.20        No.    R.sub.I      configuration                                                                              X.sub.1                                                                            X.sub.2                                                                            X.sub.3                                                                            (c =; solvent)                __________________________________________________________________________    101    (CH.sub.2).sub.4 CH.sub.3                                                                  H            CH.sub.3                                                                           H    OCH.sub.3                                                                          192                           102    (CH.sub.2).sub.4 CH.sub.3                                                                  H            OCH.sub.3                                                                          CH.sub.3                                                                           Cl   oil                           103    (CH.sub.2).sub.4 CH.sub.3                                                                  H            OCH.sub.3                                                                          OCH.sub.3                                                                          H    oil                           104    (CH.sub.2).sub.4 CH.sub.3                                                                  H            Cl   CH.sub.3                                                                           H    oil                           105    (CH.sub.2).sub.4 CH.sub.3                                                                  H            Cl   OCH.sub.3                                                                          H    oil                           106    (CH.sub.2).sub.4 CH.sub.3                                                                  H            CH.sub.3                                                                           OCH.sub.3                                                                          H    161                           107    (CH.sub.2).sub.4 CH.sub.3                                                                  CH.sub.2 CH.sub.2 CONH.sub.2 (R)                                                           CH.sub.3                                                                           H    OCH.sub.3                                                                          212                                                                           ND.sup.(1)                    108    (CH.sub.2).sub.4 CH.sub.3                                                                  CH.sub.2 CONH.sub.2 (R)                                                                    CH.sub.3                                                                           H    OCH.sub.3                                                                          170                                                                           ND                            109    (CH.sub.2).sub.4 CH.sub.3                                                                  CH.sub.3 (R) CH.sub.3                                                                           H    OCH.sub.3                                                                          oil                                                                           ND                            110    (CH.sub.2).sub.6 CH.sub.3                                                                  H            CH.sub.3                                                                           H    OCH.sub.3                                                                          169                           111    (CH.sub.2).sub.3 OCH.sub.3                                                                 H            CH.sub.3                                                                           H    OCH.sub.3                                                                          196                           112    (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                        H            OCH.sub.3                                                                          H    OCH.sub.3                                                                          120 HCl                       113                                                                                   ##STR88##   H            CH.sub.3                                                                           H    OCH.sub.3                                                                          207                           114                                                                                   ##STR89##   H            CH.sub.3                                                                           H    OCH.sub.3                                                                          190                           115                                                                                   ##STR90##   H            CH.sub.3                                                                           H    OCH.sub.3                                                                          215                           116    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR91##   CH.sub.3                                                                           H    OCH.sub.3                                                                          oil ND                        17     (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR92##   CH.sub.3                                                                           H    OCH.sub.3                                                                          oil ND                        118    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR93##   CH.sub.3                                                                           H    OCH.sub.3                                                                          90 ND                         119    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR94##   CH.sub.3                                                                           H    OCH.sub.3                                                                          oil ND                        120    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR95##   CH.sub.3                                                                           H    OCH.sub.3                                                                          oil ND                        121    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR96##   CH.sub.3                                                                           H    OCH.sub.3                                                                          oil ND                        122    (CH.sub.2).sub.4 CH.sub.3                                                                  H            Ar = 1-naphthyl                                                                              85                            123                                                                                   ##STR97##   CH.sub.3 (R) CH.sub.3                                                                           H    OCH.sub.3                                                                          oil ND                        124    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR98##   OCH.sub.3                                                                          CH.sub.3                                                                           Cl   oil -112.0 (1; CH.sub.3                                                       OH)                           125    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR99##   OCH.sub.3                                                                          CH.sub.3                                                                           H    oil -3.7 (0.8; CH.sub.3                                                       OH)                           126                                                                                   ##STR100##                                                                                 ##STR101##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil ND                        127    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR102##  CH.sub.3                                                                           Cl   H    oil ND                        128                                                                                   ##STR103##                                                                                 ##STR104##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil -3.0 (1; CH.sub.3                                                         OH)                           129                                                                                   ##STR105##                                                                                 ##STR106##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil -25.7 (1.4; CH.sub.3                                                      OH)                           130    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR107##  Cl   CH.sub.3                                                                           H    oil +81.0 (1.65; CH.sub.3                                                     OH)                           131                                                                                   ##STR108##                                                                                 ##STR109##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil ND                        132    (CH.sub.2).sub.3 CH.sub.3                                                                   ##STR110##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil ND                        133    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR111##  OCH.sub.3                                                                          H    OCH.sub.3                                                                          oil -22.1 (1; CH.sub.3                                                        OH)                           134                                                                                   ##STR112##                                                                                 ##STR113##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil -10.9 (1.15; CH.sub.3                                                     OH)                           135                                                                                   ##STR114##                                                                                 ##STR115##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil +16.0 (0.65; CH.sub.3                                                     OH)                           136    (CH.sub.2).sub.4 CH.sub.3                                                                  CH.sub.3     CH.sub.3                                                                           H    OCH.sub.3                                                                          oil                                               (S)                         ND                            137    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR116##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil -33.0 (1.17; CH.sub.3                                                     OH)                           138    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR117##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil -174.0 (1.07;                                                             CH.sub.3 OH)                  139    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR118##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil                           140    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR119##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil -28.0 (1; CH.sub.3                                                        OH)                           141    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR120##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil -32.0 (1: CH.sub.2                                                        Cl.sub.2)                     142    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR121##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil ND                        143    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR122##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil -21.2 (1; CH.sub.3                                                        OH)                           144    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR123##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil ND                        145                                                                                   ##STR124##                                                                                 ##STR125##  CH.sub.3                                                                           H    OCH.sub.3                                                                          148° C. (hydrochlor                                                    ide) -21.7 (1.05;                                                             CH.sub.3 OH)                  146    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR126##  Cl   OCH.sub.3                                                                          H    oil -5.4 (1.45; CH.sub.3                                                      OH)                           147    (CH.sub.2 CH.sub.3                                                                          ##STR127##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil -25.0 (1.15; CH.sub.3                                                     OH)                           148                                                                                   ##STR128##                                                                                 ##STR129##  CH.sub.3                                                                           H    OCH.sub.3                                                                          OIL -47.9 (1; CH.sub.3                                                        OH)                           149                                                                                   ##STR130##                                                                                 ##STR131##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil -17.9 (1; CH.sub.3                                                        OH)                           150    CH.sub.3                                                                                    ##STR132##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil -13.5 (1; CH.sub.3                                                        OH)                           151                                                                                   ##STR133##                                                                                 ##STR134##  CH.sub.3                                                                           H    OCH.sub.3                                                                          oil -30.8 (1; CH.sub.3        __________________________________________________________________________                                                    OH)                            .sup.(1) : ND:  α!.sub.D not determined                            

EXAMPLE 1 ##STR135##

0.8 9 of (2,6-dimethoxy-4-methylphenyl)(isopentyl)carbamoyl!methylaminehydrochloride (compound 100) is dissolved in 10 ml of dimethylformamideand 0.58 g of 1-(methoxycarbonylmethyl)-2-indolecarboxylic acid, 1.12 gof BOP and then, dropwise, 0.75 g of triethylamine are successivelyadded to the reaction mixture at room temperature. The reaction mixtureis left at room temperature for 20 hours, is then poured into cold waterand the aqueous phase is extracted with ethyl acetate. The organicextracts are washed with water and then dried over anhydrous sodiumsulphate. Evaporation of the solvent leaves a yellow oil which ispurified by flash chromatography on a column of silica gel, eluent:dichloromethane/methanol 98/2 (v/v) in order to obtain white crystals ofmethyl{2-(2,6-dimethoxy-4-methylphenyl)(isopentyl)carbamoyl!methylcarbamoyl!-1-indolyl}acetate;M.p.=141° C.; Yield: 91%.

EXAMPLE 2 ##STR136##

0.6 g of the ester prepared according to EXAMPLE 1 is suspended in 20 mlof methanol and 1.8 ml of a 1N aqueous sodium hydroxide solution areadded to the reaction mixture. 6 ml of dimethylformamide are added inorder to homogenize the reaction mixture and the reaction mixture isthen left for 2 hours at room temperature. The methanol is evaporatedand the residue is poured into cold water. The aqueous phase isacidified with a 1N aqueous hydrochloric acid solution and extractedwith dichloromethane. The organic extracts are washed with water anddried over anhydrous sodium sulphate. Evaporation of the solvent leaveswhite crystals of {2-(2,6-dimethoxy-4-methylphenyl)(isopentyl)carbomoyl!methylcarbomyl!-1-indolyl}aceticacid, which are washed with diisopropyl ether, M.p.=208° C.; Yield: 96%.

EXAMPLE 3 ##STR137##

0.6 g of (R)-2- (2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl!ethylaminehydrochloride (compound 109) is suspended in 10 ml of dimethylformamide.0.286 g of 1H-indole-2-carboxylic acid, 0.808 g of BOP and, dropwise,0.6 g of N-ethylmorpholine are added at 0° C. and the reaction mixtureis left at room temperature for 18 hours. The reaction mixture is pouredinto cold water and the aqeuous phase is extracted with ethyl acetate.The organic extracts are washed with water and dried over anhydroussodium sulphate. Evaporation of the solvent leaves a brown crystallineresidue which is purified by chromatography on a column of silica gel,eluent: dichloromethane/ethanol 99/1 (v/v) in order to obtain (R)-N-{1-(2,6-dimethoxy-4-methylphenyl)pentylcarbomoyl!ethyl}-1H-indole-2-carboxamide,in the form of white crystals; M.p.=193° C.; Yield: 84% α!_(D) ²⁰ =-78°(c=1, CH₂ Cl₂).

EXAMPLE 4 ##STR138##

1.5 g of(cyclohexylmethyl)(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylaminehydrochloride (compound 113) are dissolved in 10 ml of dimethylformamideand 0.918 g of 1-(2-cyanoethyl)-2-indolecarboxylic acid, 1.95 g of BOPand then, dropwise, 1.28 g of triethylamine are then successively added.The reaction mixture is left at room temperature for 3 hours, is thenpoured into cold water and the aqueous phase is extracted with ethylacetate. The organic extracts are dried over anhydrous sodium sulphateand evaporated to dryness. The residue is purified by flashchromatography on a column of silica gel, eluent:dichloromethane/methanol 98/2 (v/v) in order to obtain 3-{2-(cyclohexylmethyl)(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylcarbamoyl!-1-indolyl}propionitrilein the form of a pasty foam; Yield: 91%.

EXAMPLE 5 ##STR139##

40 ml of methanol are saturated at 0° C. (duration 30 minutes) withgaseous hydrochloric acid. 1.9 g of the nitrile prepared according toEXAMPLE 4, dissolved beforehand in 10 ml of methanol and cooled to -10°C., are introduced dropwise therein and the reaction mixture is left at-5° C. for 18 hours. Degasing is carried out and then the methanol isevaporated to dryness. The residue is taken up in a mixture of water andmethanol and the reaction mixture is left at room temperature for 3hours. Evaporation is carried out to dryness and the residue is taken upin water. The aqueous phase is extracted with ethyl acetate. The organicextracts are dried over anhydrous sodium sulphate and evaporated undervacuum to dryness. The oily residue is purified by chromatography on acolumn of silica gel, eluent: dichloromethane/methanol 98/2 (v/v) inorder to obtain white crystals of methyl 3-{2-(cyclohexylmethyl)(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylcarbamoyl!-1-indolyl}propionate;M.p.=68° C.; Yield: 92%.

EXAMPLE 6 ##STR140##

1.2 g of the ester prepared above according to EXAMPLE 5 are dissolvedin 15 ml of methanol and 3.4 ml of a 1N lithium hydroxide solution areadded. The reaction mixture is left at room temperature for 18 hours,the methanol is then evaporated and the residue is taken up in water.The aqueous phase is extracted with ethyl acetate. The organic extractsare dried over anhydrous sodium sulphate and evaporated to dryness. Thecolourless oil is crystallized from pentane in order to provide whitecrystals of 3-{2-(cyclohexylmethyl)(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylcarbamoyl!-1-indolyl}propionicacid; M.p.=110° C.; Yield: 98%.

EXAMPLE 7 ##STR141##

0.6 g of the acid prepared according to EXAMPLE 6 is dissolved in 10 mlof dimethylformamide and then 0.173 g of 2-adamantanamine, 0.505 g ofBOP and then, dropwise, 0.227 g of triethylamine are added to thereaction mixture. The reaction mixture is left at room temperature for18 hours, is then poured into water and the aqueous phase is extractedwith ethyl acetate. The organic extracts are dried over anhydrous sodiumsulphate and evaporated to dryness. The residue obtained is purified bychromatography on a column of silica gel, eluentdichloromethane/methanol 99/1 (v/v).

White crystals of N-(2-adamantyl)-3- 2-{(cyclohexylmethyl)(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylcarbamoyl}-1-indolyl!propionamideare obtained; M.p.=96° C.; Yield: 88%.

By carrying out the preparations according to EXAMPLES 1 to 7 and byusing the appropriate starting products, EXAMPLES 8 to 184 described inTABLES I to VII below are prepared.

                                      TABLE I                                     __________________________________________________________________________     ##STR142##                                                                   Example                                                                            R.sub.II and           M.p.;                                                                             α!.sup.20.sub.D                         Number                                                                             configuration                                                                              W         °C.                                                                       (c = ; solvent)                                __________________________________________________________________________     8   H            H         180                                                                              --                                              9   H            CH.sub.2 COOCH.sub.3                                                                    130                                                                              --                                             10   H            CH.sub.2 COOH                                                                           188                                                                              --                                             11   H            CH.sub.2 CH.sub.2 COOH                                                                   76                                                                              --                                             12   CH.sub.3 (R) CH.sub.2 COOCH.sub.3                                                                     73                                                                              ND                                             13   CH.sub.3 (R) CH.sub.2 COOH                                                                            98                                                                               -99.6                                                                        (1; CH.sub.3 OH)                               14   CH.sub.2 OH  H         124                                                                               -48.4                                              (R)                       (1; CH.sub.2 Cl.sub.2)                         15   CH.sub.2 COOH                                                                              H         205                                                                               -76.8                                              (R)                       (1; CHCl.sub.3)                                16   CH.sub.2 CH.sub.2                                                                          H         110                                                                               -84.6                                              COOH                      (0.9; DMF)                                          (R)                                                                      17   CH.sub.2 CH.sub.2                                                                          H         110                                                                               +67.6                                              COOH                      (0.9; DMF)                                          (S)                                                                      18                                                                                  ##STR143##  H         252                                                                               -12.7 (1.05; CH.sub.2 Cl.sub.2)               19                                                                                  ##STR144##  H         204                                                                               -8.8 (0.99; DMF)                              20                                                                                  ##STR145##  H         124                                                                               +57.0 (1; DMF)                                21                                                                                  ##STR146##  H         128                                                                               -56.2 (1; DMF)                                22                                                                                  ##STR147##  H         179                                                                               -62.2                                                                        (1; CH.sub.2 Cl.sub.2)                         23   CH.sub.2 CONH.sub.2                                                                        H         206                                                                              insoluble                                           (R)                                                                      24   CH.sub.2 CH.sub.2 CONH.sub.2                                                               H         135                                                                               -99.8                                              (R)                       (1.04;                                                                        CH.sub.2 Cl.sub.2                              25                                                                                  ##STR148##  H         193                                                                              ND                                             26   CH.sub.2 OH (R)                                                                            CH.sub.2 COOH                                                                           192                                                                               -36.6                                                                        (1; CH.sub.3 OH)                               27   CH.sub.2 COOH                                                                              CH.sub.2 COOH                                                                           115                                                                               -85.0                                              (R)                       (1, CHCl.sub.3)                                28   CH.sub.2 CH.sub.2 COOH                                                                     CH.sub.2 COOH                                                                           100                                                                               -67.7                                              (R)                       (0.9; DMF)                                     29   CH.sub.2 CH.sub.2 COOH                                                                     CH.sub.2 COOH                                                                           128                                                                               +73.3                                              (S)                       (0.9; DMF)                                     30                                                                                  ##STR149##  CH.sub.2 COOH                                                                           115                                                                               -25.6 (1.02; CH.sub.3 OH)                     31                                                                                  ##STR150##  CH.sub.2 COOH                                                                           238                                                                               -8.3 (1.02; DMF)                              32   CH.sub.2 CONH.sub.2                                                                        CH.sub.2 COOH                                                                           150                                                                               -62.7                                              (R)                       (1; CH.sub.3 OH)                               33   CH.sub.2 CH.sub.2 CONH.sub.2                                                               CH.sub.2 COOH                                                                           150                                                                              -106.4                                              (R)                       (1.17;                                                                        CH.sub.2 Cl.sub.2)                             34   CH.sub.2 OH (R)                                                                            CH.sub.2 COOCH.sub.3                                                                     87                                                                               -62.2                                                                        (1; CH.sub.3 OH)                               35   CH.sub.2 COOH                                                                              CH.sub.2 COO                                                                            104                                                                               -81.0                                              (R)          CH.sub.3     (0.99;                                                                        CHCl.sub.3)                                    36   CH.sub.2 CH.sub.2 COOH                                                                     CH.sub.2 COOCH.sub.3                                                                     80                                                                               -62.4                                              (R)                       (0.9; DMF)                                     37                                                                                  ##STR151##  CH.sub.2 COOCH.sub.3                                                                    162                                                                               -21.8 (CH.sub.3 OH)                           38                                                                                  ##STR152##  CH.sub.2 COOCH.sub.3                                                                    120                                                                               -10.6 (0.98; DMF)                             39                                                                                  ##STR153##  CH.sub.2 COOCH.sub.3                                                                     50                                                                               -47.3 (0.9; DMF)                              40                                                                                  ##STR154##  CH.sub.2 COOCH.sub.3                                                                     48                                                                               +47.0 (0.9; DMF)                              41   CH.sub.2 CONH.sub.2                                                                        CH.sub.2 COOCH.sub.3                                                                    213                                                                              -115.2                                              (R)                       (1;                                                                           CH.sub.2 Cl.sub.2)                             42   CH.sub.2 CH.sub.2 CONH.sub.2                                                               CH.sub.2 COOCH.sub.3                                                                    152                                                                               -80.8                                              (R)                       (1.02;                                                                        CH.sub.2 Cl.sub.2)                             43                                                                                  ##STR155##                                                                                 ##STR156##                                                                              66                                                                               -51.8 (1; CHCl.sub.3)                         44                                                                                  ##STR157##  CH.sub.2 COONa                                                                          154                                                                               -35.8 (0.92; CH.sub.3 OH)                     45   CH.sub.3 (S) CH.sub.2 COOCH.sub.3                                                                     72                                                                              +101.5                                                                        (1; CH.sub.3 OH)                               46   CH.sub.3 (S) CH.sub.2 COOH                                                                            94                                                                              +100.8                                                                        (1; CH.sub.3 OH)                               47   CH.sub.3 (S) H         195                                                                               +86.3                                                                        (1; CH.sub.2 Cl.sub.2)                         48   CH.sub.3 (R)                                                                                ##STR158##                                                                              86                                                                               -81.5 (0.998;CH.sub.3 OH)                     49                                                                                  ##STR159##  H         242                                                                               -29.7 (0.96; CH.sub.2 Cl.sub.2)               50                                                                                  ##STR160##  CH.sub.2 COOCH.sub.3                                                                     90                                                                               -62.2 (1.1; CH.sub.2 Cl.sub.2))               51                                                                                  ##STR161##  CH.sub.2 COONa                                                                          220                                                                               -40.2 (0.96; CH.sub.2 Cl.sub.2)               52                                                                                  ##STR162##  CH.sub.2 COOCH.sub.3                                                                     60                                                                               +47.2 (0.94; CH.sub.3 OH)                     53                                                                                  ##STR163##  H         176                                                                               +47.8 (0.93; CH.sub.2 Cl.sub.2                54   CH.sub.3 (R) CH.sub.2 CH.sub.2                                                                        67                                                                              -102.9                                                           COOH         (0.998; CH.sub.3 OH)                           55   CH.sub.3 (R) CH.sub.3   67                                                                              -114.0                                                                        (1; CH.sub.3 OH)                               56                                                                                  ##STR164##  CH.sub.2 COOLi                                                                          158                                                                               +40.0 (1; CH.sub.3 OH)                        57   CH.sub.3 (R) CH.sub.2 CH.sub.2 OH                                                                     66                                                                              -108.9                                                                        (1; CH.sub.3 OH)                               58   CH.sub.3 (R) CH.sub.2 COOCH.sub.3                                                                     60                                                                               -46.5                                                                        (1.1; CH.sub.3 OH)                             59                                                                                  ##STR165##  CH.sub.2 COOCH.sub.3                                                                     75                                                                              --                                             60                                                                                  ##STR166##  H         229                                                                              --                                             61                                                                                  ##STR167##  CH.sub.2 COOH                                                                           186                                                                              --                                             62   CH.sub.3 (R) -C.sub.2 H.sub.5                                                                         48                                                                              -116.2                                                                        (1.005; CH.sub.3 OH)                           63   CH(CH.sub.3).sub.2 (R)                                                                     H         231                                                                              -148.1                                                                        (1; DMF)                                       64   CH(CH.sub.3).sub.2 (R)                                                                     CH.sub.2 COOCH.sub.3                                                                     76                                                                              -102.5                                                                        (1; CH.sub.3 OH)                               65   CH(CH.sub.3).sub.2 (R)                                                                     CH.sub.2 COOH                                                                           192                                                                              -113.4                                                                        (1; CH.sub.3 OH)                               66                                                                                  ##STR168##  CH.sub.2 COOCH.sub.3                                                                     68                                                                               -44.0 (1; CH.sub.3 OH)                        67                                                                                  ##STR169##  H         95  -63.3 (0.92; CH.sub.3 OH)                     68   (CH.sub.2).sub.4 NH.sub.2 (R)                                                              H         134                                                                              -83,9                                                                         (0,9; CH.sub.3 OH)                             69                                                                                  ##STR170##  CH.sub.2 COOH                                                                           118                                                                               -46,5 (1; CH.sub.3 OH)                        70                                                                                  ##STR171##  CH.sub.2 CH.sub.2 COOCH.sub.3                                                           huile                                                                             -46,7 (0,8; CH.sub.3 OH)                      71                                                                                  ##STR172##  CH.sub.2 CH.sub.2 COOH                                                                   84                                                                               -45,0 (0,85; CH.sub.3 OH)                     72                                                                                  ##STR173##  CH.sub.2 COOCH.sub.3                                                                    117                                                                               -95,0 (0,995; CH.sub.3 OH)                    73                                                                                  ##STR174##  CH.sub.2 COOH                                                                            85                                                                              -100,7 (1,01 :CH.sub.3 OH)                     74                                                                                  ##STR175##  H         195                                                                               -92.5 (1; CH.sub.2 Cl.sub.2)                  75   (CH.sub.2).sub.4 NH.sub.2 (R)                                                              CH.sub.2 COOH                                                                           173                                                                              -173.0                                                                        (0.6; CH.sub.3 OH)                             76                                                                                  ##STR176##  CH.sub.2 CH.sub.3                                                                       oil                                                                               -48.3 (1; CH.sub.3 OH)                        77                                                                                  ##STR177##  CH.sub.3  107                                                                               -60.4 (1; CH.sub.3 OH)                        78                                                                                  ##STR178##  CH.sub.2 COOCH.sub.3                                                                    110                                                                               -23.7 (1.007; CH.sub.3 OH)                    79                                                                                  ##STR179##  CH.sub.2 COOCH.sub.3                                                                     66                                                                               -32.6 (0.995; CH.sub.3 OH)                    80                                                                                  ##STR180##  CH.sub.2 CH.sub.2 OH                                                                     58                                                                               -32.4 (1; CH.sub.3 OH)                        81                                                                                  ##STR181##  CH.sub.2 COOH                                                                            72                                                                               -20.6 (1; CH.sub.3 OH)                        82                                                                                  ##STR182##  CH.sub.2 COOH                                                                           101                                                                               -34.0 (1; CH.sub.3 OH)                        __________________________________________________________________________

                  TABLE II                                                        ______________________________________                                         ##STR183##                                                                   Example                                  M.p.;                                Number X.sub.1  X.sub.2 X.sub.3                                                                            W           °C.                           ______________________________________                                        83     OCH.sub.3                                                                              CH.sub.3                                                                              Cl   CH.sub.2 COOCH.sub.3                                                                      129                                  84     OCH.sub.3                                                                              CH.sub.3                                                                              Cl   H           178                                  85     OCH.sub.3                                                                              CH.sub.3                                                                              Cl   CH.sub.2 COOH                                                                             175                                  86     Cl       CH.sub.3                                                                              H    CH.sub.2 COOCH.sub.3                                                                      90                                   87     Cl       CH.sub.3                                                                              H    H           189                                  88     Cl       CH.sub.3                                                                              H    CH.sub.2 COOH                                                                             197                                  89     Cl       OCH.sub.3                                                                             H    H           194                                  90     Cl       OCH.sub.3                                                                             H    CH.sub.2 COOCH.sub.3                                                                      132                                  91     Cl       OCH.sub.3                                                                             H    CH.sub.2 COOH                                                                             118                                  92     CH.sub.3 Cl      H    H           196                                  93     CH.sub.3 Cl      H    CH.sub.2 COOCH.sub.3                                                                      116                                  94     CH.sub.3 Cl      H    CH.sub.2COO.sup.- Na.sup.+                                                                115                                  ______________________________________                                    

                  TABLE III                                                       ______________________________________                                         ##STR184##                                                                   Example                              M.p.;                                    Number    X.sub.1 X.sub.2   W        °C.                               ______________________________________                                        95        OCH.sub.3                                                                             CH.sub.3  H        61                                       96        OCH.sub.3                                                                             CH.sub.3  CH.sub.2 COOH                                                                          130                                      97        CH.sub.3                                                                              OCH.sub.3 H        189                                      98        OCH.sub.3                                                                             OCH.sub.3 CH.sub.2 COOCH.sub.3                                                                   51                                       99        OCH.sub.3                                                                             OCH.sub.3 CH.sub.2 COOH                                                                          202                                      100       OCH.sub.3                                                                             OCH.sub.3 H        199                                      101       CH.sub.3                                                                              OCH.sub.3 CH.sub.2 COOCH.sub.3                                                                   110                                      102       CH.sub.3                                                                              OCH.sub.3                                                                                ##STR185##                                                                            76                                       103       CH.sub.3                                                                              OCH.sub.3 CH.sub.2 COOH                                                                          166                                      ______________________________________                                    

                                      TABLE IV                                    __________________________________________________________________________     ##STR186##                                                                   Example                                M.p.;                                  Number                                                                              R.sub.I      W         X.sub.1                                                                            X.sub.2                                                                            °C.                             __________________________________________________________________________    104   (CH.sub.2).sub.6 CH.sub.3                                                                  H         CH.sub.3                                                                           OCH.sub.3                                                                          129                                    105   (CH.sub.2).sub.6 CH.sub.3                                                                  CH.sub.2 COOH                                                                           CH.sub.3                                                                           OCH.sub.3                                                                          178                                    106   (CH.sub.2).sub.6 CH.sub.3                                                                  (CH.sub.2).sub.2 COOCH.sub.3                                                            CH.sub.3                                                                           OCH.sub.3                                                                          91                                     107   (CH.sub.2).sub.6 CH.sub.3                                                                  (CH.sub.2).sub.2 COOH                                                                   CH.sub.3                                                                           OCH.sub.3                                                                          85                                     108   (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                        H         CH.sub.3                                                                           OCH.sub.3                                                                          199                                    109   (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                        H         OCH.sub.3                                                                          OCH.sub.3                                                                          188                                    110   (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                        CH.sub.2 COOH                                                                           OCH.sub.3                                                                          OCH.sub.3                                                                          226                                    111                                                                                  ##STR187##  H         CH.sub.3                                                                           OCH.sub.3                                                                          225                                    112                                                                                  ##STR188##  CH.sub.2 COO.sup.- Na.sup.+                                                             CH.sub.3                                                                           OCH.sub.3                                                                          235                                    113                                                                                  ##STR189##  H         CH.sub.3                                                                           OCH.sub.3                                                                          238                                    114                                                                                  ##STR190##  CH.sub.2 COOCH.sub.3                                                                    OCH.sub.3                                                                          H    163                                    115                                                                                  ##STR191##  CH.sub.2 COOH                                                                           OCH.sub.3                                                                          H    198                                    116                                                                                  ##STR192##  H         CH.sub.3                                                                           OCH.sub.3                                                                          234                                    117                                                                                  ##STR193##  CH.sub.2 COOCH.sub.3                                                                    CH.sub.3                                                                           OCH.sub.3                                                                          161                                    118                                                                                  ##STR194##  CH.sub.2 COOH                                                                           CH.sub.3                                                                           OCH.sub.3                                                                          212                                    119                                                                                  ##STR195##                                                                                 ##STR196##                                                                             CH.sub.3                                                                           OCH.sub.3                                                                          196                                    120   (CH.sub.2).sub.3 OCH.sub.3                                                                 H         CH.sub.3                                                                           OCH.sub.3                                                                          198                                    121   (CH.sub.2).sub.3 OCH.sub.3                                                                 CH.sub.2 COOH                                                                           CH.sub.3                                                                           OCH.sub.3                                                                          202                                    122   (CH.sub.2).sub.3 OCH.sub.3                                                                 CH.sub.2 COOCH.sub.3                                                                    CH.sub.3                                                                           OCH.sub.3                                                                          76                                     123   (CH.sub.2).sub.3 OCH.sub.3                                                                 (CH.sub.2).sub.2 COOH                                                                   CH.sub.3                                                                           OCH.sub.3                                                                          103                                    124   (CH.sub.2).sub.3 OCH.sub.3                                                                 (CH.sub.2).sub.2 COOCH.sub.3                                                            CH.sub.3                                                                           OCH.sub.3                                                                          94                                     125   (CH.sub.2).sub.2 CH(CH.sub.3).sub.2                                                        CH.sub.2 COOH                                                                           OCH.sub.3                                                                          OCH.sub.3                                                                          226                                    __________________________________________________________________________     Note: (1) 2ada represents the 2adamantyl group                           

                  TABLE V                                                         ______________________________________                                         ##STR197##                                                                   Example                                                                       Number R.sub.I      R.sub.III       M.p.; °C.                          ______________________________________                                        126    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR198##     136                                       127    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR199##     173                                       128    (CH.sub.2).sub.4 CH.sub.3                                                                   ##STR200##     173                                       129    (CH.sub.2).sub.6 CH.sub.3                                                                   ##STR201##     108                                       130    (CH.sub.2).sub.6 CH.sub.3                                                                   ##STR202##     150                                       131    (CH.sub.2).sub.6 CH.sub.3                                                                   ##STR203##      98                                       132    (CH.sub.2).sub.6 CH.sub.3                                                                   ##STR204##     122                                       133    (CH.sub.2).sub.3 OCH.sub.3                                                                  ##STR205##     101                                       134    (CH.sub.2).sub.3 OCH.sub.3                                                                  ##STR206##     134                                       135    (CH.sub.2).sub.3 OCH.sub.3                                                                  ##STR207##     176                                       136    (CH.sub.2).sub.3 OCH.sub.3                                                                  ##STR208##     174                                       137    (CH.sub.2).sub.3 OCH.sub.3                                                                  ##STR209##     167                                       ______________________________________                                    

                  TABLE VI                                                        ______________________________________                                         ##STR210##                                                                   Example                W            M.p.;                                     Number  Ar             W            °C.                                ______________________________________                                        138                                                                                    ##STR211##    CH.sub.2 COOCH.sub.3                                                                        71                                       139                                                                                    ##STR212##    CH.sub.2 COOH                                                                              159                                       ______________________________________                                    

                                      TABLE VII                                   __________________________________________________________________________     ##STR213##                                                                                    R.sub.II and                   M.p.; °C.              Example          confi-                          α!.sub.D.sup.20        Number                                                                             R.sub.I     guration   X.sub.1                                                                           X.sub.2                                                                           X.sub.3                                                                           W       (c=; solvent)                 __________________________________________________________________________    140                                                                                 ##STR214## CH.sub.3 (R)                                                                             CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOCH.sub.3                                                                  130 -87.4 (1; CH.sub.3                                                        OH)                           141                                                                                 ##STR215## CH.sub.3 (R)                                                                             CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOH                                                                         171 -87.3 (1; CH.sub.3                                                        OH)                           142                                                                                 ##STR216## CH.sub.3 (R)                                                                             CH.sub.3                                                                          H   OCH.sub.3                                                                         H       252 -81.5 (1; CH.sub.2                                                        Cl.sub.2)                     143  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR217##                                                                              OCH.sub.3                                                                         CH.sub.3                                                                          Cl  H       92 -74.4 (1.1; CH.sub.3                                                       OH)                           144  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR218##                                                                              OCH.sub.3                                                                         CH.sub.3                                                                          H   CH.sub.2 COOCH.sub.3                                                                  78 -88.2 (1.4; CH.sub.3                                                       OH)                           145  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR219##                                                                              OCH.sub.3                                                                         CH.sub.3                                                                          Cl  CH.sub.2 COOH                                                                         89 -59.3 (0.85; CH.sub.3                                                      OH)                           146  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR220##                                                                              OCH.sub.3                                                                         CH.sub.3                                                                          H   H       190 -104.0 (0.75;                                                             CH.sub.3 OH)                  147  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR221##                                                                              OCH.sub.3                                                                         CH.sub.3                                                                          H   CH.sub.2 COOH                                                                         72 -66.5 (1; CH.sub.3                                                         OH)                           148                                                                                 ##STR222##                                                                                ##STR223##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOH                                                                         110 -54.0 (1.05; CH.sub.3                                                     OH)                           149  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR224##                                                                              OCH.sub.3                                                                         CH.sub.3                                                                          Cl  CH.sub.2 COOCH.sub.3                                                                  55 -88.2 (1.1; CH.sub.3                                                       OH)                           150                                                                                 ##STR225##                                                                                ##STR226##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 CO.sub.2 CH.sub.3                                                            78 -50.0 (0.985; CH.sub.3                                                     OH)                           151  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR227##                                                                              CH.sub.3                                                                          Cl  H   H       186 -13.0 (1; DMF)            152  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR228##                                                                              CH.sub.3                                                                          Cl  H   CH.sub.2 COOH                                                                         205 -6.0 (1.1; DMF)           153  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR229##                                                                              CH.sub.3                                                                          Cl  H   CH.sub.2 COOCH.sub.3                                                                  60 -6.0 (1.125; CH.sub.3                                                      OH)                           154                                                                                 ##STR230##                                                                                ##STR231##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOCH.sub.3                                                                  80 -45.0 (1.07; CH.sub.3                                                      OH)                           155                                                                                 ##STR232##                                                                                ##STR233##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOH                                                                         112 -45.0 (1; CH.sub.3                                                        OH)                           156                                                                                 ##STR234##                                                                                ##STR235##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         H       185 -70.0 (0.95; DMF)         157                                                                                 ##STR236##                                                                                ##STR237##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOCH.sub.3                                                                  68 -31.5 (1; CH.sub.3                                                         OH)                           158                                                                                 ##STR238##                                                                                ##STR239##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         H       157 -33.0 (1; CH.sub.3                                                        OH)                           159  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR240##                                                                              Cl  CH.sub.3                                                                          H   CH.sub.2 COOCH.sub.3                                                                  70 -19.0 (1.025; CH.sub.3                                                     OH)                           160                                                                                 ##STR241##                                                                                ##STR242##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOH                                                                         124 -33.0 (1; CH.sub.3                                                        OH)                           161  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR243##                                                                              Cl  CH.sub.3                                                                          H   CH.sub.2 COOH                                                                         135 -19.0 (1.15; CH.sub.3                                                     OH)                           162  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR244##                                                                              Cl  CH.sub.3                                                                          H   H       186 -14.0 (0.95; CH.sub.2                                                     Cl.sub.2)                     163                                                                                 ##STR245##                                                                                ##STR246##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOCH.sub.3                                                                  73 -80.2 (1; CH.sub.3                                                         OH)                           164  (CH.sub.2).sub.3 CH.sub.3                                                                  ##STR247##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOCH.sub.3                                                                  60 -35.5 (1; CH.sub.3                                                         OH)                           165                                                                                 ##STR248##                                                                                ##STR249##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOH                                                                         112 -79.5 (1; CH.sub.3                                                        OH)                           166  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR250##                                                                              OCH.sub.3                                                                         H   OCH.sub.3                                                                         CH.sub.2 COOCH.sub.3                                                                  58 -58.3 (1; CH.sub.3                                                         OH)                           167  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR251##                                                                              OCH.sub.3                                                                         H   OCH.sub.3                                                                         CH.sub.2 COOH                                                                         99 -61.1 (1; CH.sub.3                                                         OH)                           168                                                                                 ##STR252##                                                                                ##STR253##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOH                                                                         165 -52.0 (0.805;                                                             CH.sub.3 OH)                  169                                                                                 ##STR254##                                                                                ##STR255##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOCH.sub.3                                                                  130 -49.0 (0.9; CH.sub.3                                                      OH)                           170                                                                                 ##STR256##                                                                                ##STR257##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOCH.sub.3                                                                  120 -60.0 (0.97; CH.sub.3                                                     OH)                           171                                                                                 ##STR258##                                                                                ##STR259##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOH                                                                         165 -55.0 (0.925;                                                             CH.sub.3 OH)                  172  (CH.sub.2).sub.3 CH.sub.3                                                                  ##STR260##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOH                                                                         81 -55.1 (1; CH.sub.3                                                         OH)                           173  CH.sub.2 CH.sub.3                                                                          ##STR261##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOCH.sub.3                                                                  71 -59.3 (1; CH.sub.3                                                         OH)                           174  CH.sub.2 CH.sub.3                                                                          ##STR262##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOLi                                                                        100 -63.0 (1; CH.sub.3                                                        OH)                           175                                                                                 ##STR263##                                                                                ##STR264##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOCH.sub.3                                                                  107 -73.7 (1; CH.sub.3                                                        OH)                           176                                                                                 ##STR265##                                                                                ##STR266##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOCH.sub.3                                                                  150 -56.0 (0.925;                                                             CH.sub.3 OH)                  177  (CH.sub.2).sub.4 CH.sub.3                                                                  ##STR267##                                                                              Cl  OCH.sub.3                                                                         H   CH.sub.2 COOCH.sub.3                                                                  70 -88.2 (0.97; CH.sub.3                                                      OH)                           178                                                                                 ##STR268##                                                                                ##STR269##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOH                                                                         153 -78.4 (1; CH.sub.3                                                        OH)                           179                                                                                 ##STR270##                                                                                ##STR271##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOCH.sub.3                                                                  74 -53.3 (1; CH.sub.3                                                         OH)                           180  CH.sub.3                                                                                   ##STR272##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOCH.sub.3                                                                  64 -50.0 (1; CH.sub.3                                                         OH)                           181                                                                                 ##STR273##                                                                                ##STR274##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOH                                                                         110 -36.8 (1; CH.sub.3                                                        OH)                           182                                                                                 ##STR275##                                                                                ##STR276##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOH                                                                         126 -65.0 (1; CH.sub.3                                                        OH)                           183  CH.sub.3                                                                                   ##STR277##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOH                                                                         103 -58.6 (1; CH.sub.3                                                        OH)                           184                                                                                 ##STR278##                                                                                ##STR279##                                                                              CH.sub.3                                                                          H   OCH.sub.3                                                                         CH.sub.2 COOCH.sub.3                                                                  76 -57.8 (1; CH.sub.3         __________________________________________________________________________                                                    OH)                       

EXAMPLE 185

Methyl 2-{butyl(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylcarbamoyl}-1-indolyl!acetate.##STR280##

This product is prepared according to the process described in EXAMPLE 1from butyl(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylamine and1-(methoxycarbonylmethyl)-2-indolecarboxylic acid; M.p.=139° C.; Yield:90%.

EXAMPLE 186 ##STR281##

By carrying out the preparation according to EXAMPLE 2, from methyl{2-butyl(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylcarbamoyl!-1-indolyl}acetate(EXAMPLE 185), {2-butyl(2,6-dimethoxy-4-methylphenyl)carbamoyl!methylcarbamoyl!-1-indolyl}aceticacid is prepared; M.p.=211° C.; Yield: 92%.

EXAMPLE 187 ##STR282##

By carrying out the preparation according to EXAMPLE 3, N-{((methylphenylcarbamoyl)methyl)(2,6-dimethoxy-4-methylphenyl)carbamoyl!methyl}-1H-indole-2-carboxamideis prepared, M.p.=116° C.; Yield: 90%.

EXAMPLE 188 ##STR283##

By carrying out the preparation according to EXAMPLE 3, N-butyl(2,6-dimethoxy-4-methylphenyl)carbamoyl!methyl!-1H-indole-2-carboxamideis prepared; M.p.=210° C.; Yield: 91%.

EXAMPLE 189 ##STR284##

5.6 g of methyl (R)-{2- N-{1-(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl!-5-(benzyloxycarbonylamino)pentyl}carbamoyl!indol-1-yl}acetate(EXAMPLE 66) are dissolved in 170 ml of methanol and 0.56 g of 10% Pd/Cis added thereto. Hydrogenation is carried out under a pressure of 3 barand the reaction mixture is left at 30° C., while maintaining thispressure, for 18 hours. After cooling, the catalyst is filtered over abed of celite and evaporation is carried out to dryness. The residualoil is purified by flash chromatography on silica gel, eluent: CH₂ Cl₂/CH₃ OH/AcOH 90/10/0.5 (v/v/v) in order to obtain white crystals ofmethyl (R)-{2- N-{1-(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl!-5-aminopentyl}carbamoyl!indol-1-yl}acetate,M.p.=78° C., α!_(D) ²⁰ =-47.6° (c=1, CH₃ OH), Yield: 85%.

EXAMPLE 190 ##STR285##

0.7 g of the compound prepared in EXAMPLE 189 above is dissolved in 20ml of methanol and 0.075 g of lithium hydroxide hydrate is added and thereaction mixture is left at room temperature for 18 hours. Evaporationis carried out to dryness and the residue is taken up in water. Theaqueous phase is acidified with 1N HCl and extraction is carried outwith ethyl acetate. The organic extracts are dried over anhydrous sodiumsulphate and evaporated to dryness. The crystals obtained are purifiedby flash chromatography on silica gel, eluent: CH₂ Cl₂ /CH₃ OH, 9/1(v/v) in order to obtain white crystals of (R)-{2- N-{1-(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl!-5-aminopentyl}carbamoyl!indol-1-yl}aceticacid, M.p.=173° C., α!_(D) ²⁰ =-173.0° (c=0.6, CH₃ OH), Yield: 87%.

EXAMPLE 191 ##STR286##

0.87 g of methyl (R)-{2- N-{1-(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl!-5-aminopentyl}carbamoyl!indol-1-yl}acetate,0.645 g of BOP and 0.23 g of cinnamic acid are successively added to 30ml of dimethylformamide. After cooling to -5° C., 0.26 g ofN-ethylmorpholine is added under an inert atmosphere and the reactionmixture is maintained at 0° C. for 2 hours and is then left at roomtemperature for 18 hours. The reaction mixture is poured into a largevolume of water and extraction is carried out with ethyl acetate. Theorganic extracts are dried over anhydrous sodium sulphate and evaporatedto dryness. The residual oil is purified by flash chromatography onsilica gel, eluent: CH₂ Cl₂ /CH₃ OH 97/3 (v/v) in order to obtain methyl(R)-{2- N-{1-(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl!-5-(cinnamoylamino)pentyl}carbamoyl!indol-1-yl}acetatein the form of an oil.

EXAMPLE 192 ##STR287##

The preceding ester is saponified with LiOH.H₂ O/CH₃ OH, as previously,in order to provide white crystals of (R)-{2- N-{1-(2,6-dimethoxy-4-methylphenyl)pentylcarbamoyl!-5-(cinnamoylamino)pentyl}carbamoyl!indol-1-yl}aceticacid, M.p.=172° C., α!²⁰ _(D) =-21.2° (c=0.8, CH₃ OH).

We claim:
 1. Compound of formula: ##STR288## in which R_(I) represents a(C₃ -C₈) alkyl; an arylalkyl -Alk-Ar₁, where Alk represents an alkylenecontaining 1 to 4 carbon atoms and Ar₁ represents a phenyl group or aheterocycle optionally substituted by a halogen, a (C₁ -C₃) alkyl, a (C₁-C₃) alkoxy, a trifluoromethyl or a hydroxyl; a cycloalkylalkyl in whichthe alkyl is (C₁ -C₄) and the cycloalkyl is (C₃ -C₁₀); a (C₃ -C₁₀)cycloalkyl optionally substituted by a hydroxyl, a (C₁ -C₃) alkoxy or a(C₁ -C₃) alkyl, it being possible for the said alkyl to substitute thesame carbon atom twice; an alkoxyalkyl in which the alkoxy is (C₁ -C₄)and the alkyl is (C₂ -C₅); or a group (AB)N--CO--(CH₂)_(r) --, where Ais a (C₁ -C₃) alkyl, B is a (C₁ -C₃) alkyl or a phenyl or else A and Bform, with the nitrogen atom to which they are bonded, a heterocyclechosen from pyrrolidine, piperidine and morpholine, and R is 1, 2 or3;R_(II) represents hydrogen; a (C₁ -C₆) alkyl; a (C₁ -C₅) hydroxyalkyl;a group --(CH₂)_(m) --COR₂ in which m is an integer from 1 to 3 and R₂represents a hydroxyl, a (C₁ -C₄) alkoxy group, a benzyloxy group or agroup --NR₃ R₄ in which R₃ or R₄ independently represent hydrogen, a (C₁-C₄) alkyl or constitute, with the nitrogen atom to which they arebonded, a heterocycle chosen from pyrrolidine, piperidine andmorpholine; an aralkyl group --(CH₂)_(n) --Ar₂ in which n is equal to 0or represents an integer from 1 to 4 and Ar_(r) represents a phenyl or aheterocycle optionally substituted by a halogen, a (C₁ -C₃) alkyl, a (C₁-C₃) alkoxy, a trifluoromethyl, a hydroxyl or a benzyloxy; acycloalkylalkyl in which the alkyl is (C₁ -C₄) and the cycloalkyl is (C₃-C₁₀); a (C₁ -C₄) aminoalkyl; a group R--CO--NH--(CH₂)_(x) -- in which xrepresents an integer from 1 to 4 and R represents a (C₁ -C₄) alkyl, aphenyl, a benzyl, a 2-phenylethenyl or a benzyloxy, the aromatic ringsoptionally being substituted by a halogen, a (C₁ -C₃) alkyl, a (C₁ -C₃)alkoxy, a trifluoromethyl, a hydroxyl or a sulpho or carboxyl group; aguanidino(C₁ -C₄)alkyl; an imidazolyl (C₁ -C₃) alkyl; an alkylthioalkylin which the alkyls are (C₁ -C₃); an aralkylthioalkyl in which the arylpart is optionally heterocyclic and the alkyl parts are (C₁ -C₃), thearyl optionally being substituted by a halogen, a (C₁ -C₃) alkyl, a (C₁-C₃) alkoxy, a trifluoromethyl or a hydroxyl; a benzyloxyalkyl in whichthe alkyl is (C₁ -C₃) and the phenyl is optionally substituted by ahalogen, a hydroxyl, a (C₁ -C₃) alkoxy, a (C₁ -C₃) alkyl, atrifluoromethyl, a nitrile or a nitro; R_(III) represents an indolylgroup which is unsubstituted, substituted on a carbon or substituted onthe nitrogen by a (C₁ -C₃) alkyl or (C₁ -C₄) alkylcarbonyl group, by agroup --(CH₂)_(p) --COR₅, p being an integer from 0 to 4 and R₅representing OR'₅ or NR'₅ R"₅ with R'₅ and R"₅, which may or may not beidentical, representing hydrogen or a (C₁ -C₄) alkyl or else R'₅ and R"₅form, together with the nitrogen atom to which they are bonded, apiperidine, by a (C₁ -C₄) hydroxyalkyl, by a (C₂ -C₆) alkoxyalkyl, by a(C₂ -C₄) cyanoalkyl, by a tetrahydropyranyl, by a (C₁ -C₄)adamantylaminocarbonylalkyl or by a chain --(CH₂)_(q) --, q being aninteger from 2 to 4, one of the carbons of which substitutes the phenylring of the indole group in order to constitute a ring; Ar represents2-methoxyphenyl group containing at least two other substituents chosenfrom a (C₁ -C₃) alkyl, a (C₁ -C₃) alkoxy, a halogen atom and atrifluoromethyl; or Ar represents a naphthyl group;or optionally one oftheir salts.
 2. Compound according to claim 1, of formula: ##STR289## inwhich R_(II) and R_(III) are as defined in claim 1 for (I) and R_(Ia)represents a (C₅ -C₈) alkyl; an arylalkyl -Alk-Ar₁, where Alk representsan alkylene containing 1 to 4 carbon atoms and Ar₁ represents a phenylgroup or a heterocycle optionally substituted by a halogen, a (C₁ -C₃)alkyl, a (C₁ -C₃) alkoxy, a trifluoromethyl or a hydroxyl; acycloalkylalkyl in which the alkyl is (C₁ -C₄) and the cycloalkyl is (C₃-C₁₀); a (C₃ -C₁₀) cycloalkyl which is optionally substituted by ahydroxyl, a (C₁ -C₃) alkoxy, or a (C₁ -C₃) alkyl, it being possible forthe said alkyl to substitute the same carbon atom twice; an alkoxyalkylin which the alkoxy is (C₁ -C₄) and the alkyl is (C₂ -C₅); or a group(AB)N--CO--(CH₂)_(r) --, where A is a (C₁ -C₃) alkyl, B is a (C₁ -C₃)alkyl or a phenyl or else A and B form, with the nitrogen atom to whichthey are bonded, a heterocycle chosen from pyrrolidine, piperidine andmorpholine, and r is 1, 2 or 3; or a salt thereof.
 3. Compound accordingto claim 1 of formula (I) in which Ar represents a naphthyl group andR_(I) represents a (C₅ -C₈) alkyl; an arylalkyl -Alk-Ar₁, where Alkrepresents an alkylene containing 1 to 4 carbon atoms and Ar₁ representsa phenyl group or a heterocycle optionally substituted by a halogen, a(C₁ -C₃) alkyl, a (C₁ -C₃) alkoxy, a trifluoromethyl or a hydroxyl; acycloalkylalkyl in which the alkyl is (C₁ -C₄) and the cycloalkyl is (C₃-C₁₀); a (C₃ -C₁₀) cycloalkyl which is optionally substituted by ahydroxyl, a (C₁ -C₃) alkoxy, or a (C₁ -C₃) alkyl, it being possible forthe said alkyl to substitute the same carbon atom twice; an alkoxyalkylin which the alkoxy is (C₁ -C₄) and the alkyl is (C₂ -C₅); or a group(AB)N--CO--(CH₂)_(r) --, where A is a (C₁ -C₃) alkyl, B is a (C₁ -C₃)alkyl or a phenyl or else A and B form, with the nitrogen atom to whichthey are bonded, a heterocycle chosen from pyrrolidine, piperidine andmorpholine, and r is 1, 2 or 3; or a salt thereof.
 4. Compound accordingto claim 1, of formula (I) in which R_(II), is other than hydrogen andin which the carbon carrying the substituent R_(II) is in the Rconfiguration or a salt thereof.
 5. Pharmaceutical compositioncontaining, as active principle, a compound according to claim 1 incombination with a pharmaceutically acceptable vehicle. 6.Pharmaceutical composition according to claim 5, in unit dosage form, inwhich the pharmaceutically acceptable vehicle is at least onepharmaceutical excipient.
 7. Pharmaceutical composition according toclaim 6, containing from 0.5 to 1,000 mg of the active principle. 8.Compound of formula: ##STR290## in which R_(I) represents a (C₃ -C₈)alkyl; an arylalkyl -Alk-Ar₁, where Alk represents an alkylenecontaining 1 to 4 carbon atoms and Ar₁ represents a phenyl group or aheterocycle optionally substituted by a halogen, a (C₁ -C₃) alkyl, a (C₁-C₃) alkoxy, a trifluoromethyl or a hydroxyl; a cycloalkylalkyl in whichthe alkyl is (C₁ -C₄) and the cycloalkyl is (C₃ -C₁₀); a (C₃ -C₁₀)cycloalkyl optionally substituted by a hydroxyl, a (C₁ -C₃) alkoxy or a(C₁ -C₃) alkyl, it being possible for the said alkyl to substitute thesame carbon atom twice; an alkoxyalkyl in which the alkoxy is (C₁ -C₄)and the alkyl is (C₂ -C₅);R_(II) represents hydrogen; a (C₁ -C₆) alkyl;a (C₁ -C₅) hydroxyalkyl; an aralkyl group --(CH₂)_(n) --Ar₂ in which nis equal to 0 or represents an integer from 1 to 4 and Ar₂ represents aheterocycle optionally substituted by a halogen, a (C₁ -C₃) alkyl, a (C₁-C₃) alkoxy, a trifluoromethyl, a hydroxyl or a benzyloxy; acycloalkylalkyl in which the alkyl is (C₁ -C₄) and the cycloalkyl is (C₃-C₁₀); a (C₁ -C₄) aminoalkyl; a group R--CO--NH--(CH₂)_(x) -- in which xrepresents an integer from 1 to 4 and R represents a (C₁ -C₄) alkyl, aphenyl, a benzyl, a 2-phenylethenyl or a benzyloxy, the aromatic ringsoptionally being substituted by a halogen, a (C₁ -C₃) alkyl, a (C₁ -C₃)alkoxy, a trifluoromethyl, a hydroxyl or a sulpho or carboxyl group; aguanidino(C₁ -C₄)alkyl; an imidazolyl (C₁ -C₃) alkyl; an alkylthioalkylin which the alkyls are (C₁ -C₃); an aralkylthioalkyl in which the arylpart is optionally heterocyclic and the alkyl parts are (C₁ -C₃), thearyl optionally being substituted by a halogen, a (C₁ -C₃) alkyl, a (C₁-C₃) alkoxy, a trifluoromethyl or a hydroxyl; a benzyloxalkyl in whichthe alkyl is (C₁ -C₃ and the phenyl is optionally substituted by ahalogen, a hydroxyl, a (C₁ -C₃) alkoxy, a (C₁ -C₃) alkyl, atrifluoromethyl, a nitrile or a nitro; R_(III) represents an indolylgroup which is unsubstituted, substituted on a carbon or substituted onthe nitrogen by a (C₁ -C₃) alkyl or (C₁ -C₄) alkylcarbonyl group, by agroup --(CH₂)_(p) --COR₅, p being an integer from 0 to 4 and R₅representing OR'₅ or NR'₅ R"₅ with R'₅ and R"₅, which may or may not beidentical, representing hydrogen or a (C₁ -C₄) alkyl or else R'₅ and R"₅form, together with the nitrogen atom to which they are bonded, apiperidine, by a (C₁ -C₄) hydroxyalkyl, by a (C₂ -C₆) alkoxyalkyl, by a(C₂ -C₄) cyanoalkyl, by a tetrahydropyranyl, by a (C₁ -C₄)adamantylaminocarbonylalkyl or by a chain --(CH₂)_(q) --, q being aninteger from 2 to 4, one of the carbons of which substitutes the phenylring of the indole group in order to constitute a ring; Ar represents2-methoxyphenyl group containing at least two other substituents chosenfrom a (C₁ -C₃) alkyl, a (C₁ -C₃) alkoxy, a halogen atom and atrifluoromethyl; or Ar represents a naphthyl group;or a salt thereof. 9.Compound of formula: ##STR291## in which R_(I) represents a (C₃ -C₈)alkyl; an arylalkyl -Alk-Ar₁, where Alk represents an alkylenecontaining 1 to 4 carbon atoms and Ar₁ represents a phenyl group or aheterocycle optionally substituted by a halogen, a (C₁ -C₃) alkyl, a (C₁-C₃) alkoxy, a trifluoromethyl or a hydroxyl; a cycloalkylalkyl in whichthe alkyl is (C₁ -C₄) and the cycloalkyl is (C₃ -C₁₀); a (C₃ -C₁₀)cycloalkyl optionally substituted by a hydroxyl, a (C₁ -C₃) alkoxy or a(C₁ -C₃) alkyl, it being possible for the said alkyl to substitute thesame carbon atom twice; or an alkoxyalkyl in which the alkoxy is (C₁-C₄) and the alkyl is (C₂ -C₅);R_(II) represents hydrogen; a (C₁ -C₆)alkyl; a (C₁ -C₅) hydroxylalkyl; a cycloalkylalkyl in which the alkyl is(C₁ -C₄) and the cycloalkyl is (C₃ -C₁₀); a (C₁ -C₄) aminoalkyl; a groupR--CO--NH--(CH₂)_(x) -- in which x represents an integer from 1 to 4 andR represents a (C₁ -C₄) alkyl, a phenyl, a benzyl, a 2-phenylethenyl ora benzyloxy, the aromatic rings optionally being substituted by ahalogen, a (C₁ -C₃) alkyl, a (C₁ -C₃) alkoxy, a trifluoromethyl, ahydroxyl or a sulpho or carboxyl group; a guanidino(C₁ -C₄)alkyl; animidazolyl (C₁ -C₃) alkyl; an alkylthioakyl in which the alkyls are (C₁-C₃); an aralkylthioalkyl in which the aryl part is optionallyheterocyclic and the alkyl parts are (C₁ -C₃), the aryl optionally beingsubstituted by a halogen, a (C₁ -C₃) alkyl, a (C₁ -C₃) alkoxy, atrifluoromethyl or a hydroxyl; a benzyloxyalkyl in which the alkyl is(C₁ -C₃) and the phenyl is optionally substituted by a halogen, ahydroxyl, a (C₁ -C₃) alkoxy, a (C₁ -C₃) alkyl, a trifluoromethyl, anitrile or a nitro; R_(III) represents an indolyl group which isunsubstituted, substituted on a carbon or substituted on the nitrogen bya (C₁ -C₃) alkyl or (C₁ -C₄) alkylcarbonyl group, by a group --(CH₂)_(p)--COR₅, p being an integer from 0 to 4 and R₅ representing OR'₅ or N'₅RR"₅ with R'₅ and R"₅, which may or may not be identical, representinghydrogen or a (C₁ -C₄) alkyl or else R'₅ and R"₅ form, together with thenitrogen atom to which they are bonded, a piperidine, by a (C₁ -C₄)hydroxyalkyl, by a (C₂ -C₆) alkoxyalkyl, by a (C₂ -C₄) cyanoalkyl, by atetrahydropyranyl, by a (C₁ -C₄) adamantylaminocarbonylalkyl or by achain --(CH₂)_(q) --, q being an integer from 2 to 4, one of the carbonsof which substitutes the phenyl ring of the indole group in order toconstitute a ring; Ar represents 2-methoxyphenyl group containing atleast two other substitutents chosen from (C₁ -C₃) alkyl, a (C₁ -C₃)alkoxy, a halogen atom and a trifluoromethyl; or Ar represents anaphthyl group;or a salt thereof.
 10. Process for the preparation of acompound according to claim 1 of formula (I), characterized in that anamine of formula: ##STR292## in which Ar and R_(I) are as defined above,is treated with an N-protected amino acid of formula: ##STR293## inwhich R_(II) is as defined for (I) and in which, if appropriate, thereactive groups of R_(II) have been protected, in order to lead to acompound of formula: ##STR294## in which R_(I), Ar and R_(II) are asdefined above, which, after conversion, leads to a compound (I)according to claim 1 or one of its optional salts.